U.S. patent application number 13/078573 was filed with the patent office on 2011-10-06 for combination with bis (thiohydrazide amides) for treating cancer.
This patent application is currently assigned to Synta Pharmaceuticals Corp.. Invention is credited to Keizo Koya.
Application Number | 20110245577 13/078573 |
Document ID | / |
Family ID | 39004875 |
Filed Date | 2011-10-06 |
United States Patent
Application |
20110245577 |
Kind Code |
A1 |
Koya; Keizo |
October 6, 2011 |
COMBINATION WITH BIS (THIOHYDRAZIDE AMIDES) FOR TREATING CANCER
Abstract
Disclosed herein are methods of treating a proliferative
disease, such as cancer, with bis(thio-hydrazide amides) or a
tautomer, pharmaceutically acceptable salt, solvate, clathrate, or
prodrug thereof, in combination with hyperthermia treatment. Also
disclosed are methods of treating a proliferative disease, such as
cancer, with bis(thio-hydrazide amides) or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate, or prodrug
thereof, in combination with radiotherapy.
Inventors: |
Koya; Keizo; (Chestnut Hill,
MA) |
Assignee: |
Synta Pharmaceuticals Corp.
|
Family ID: |
39004875 |
Appl. No.: |
13/078573 |
Filed: |
April 1, 2011 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11897538 |
Aug 30, 2007 |
7939564 |
|
|
13078573 |
|
|
|
|
60841570 |
Aug 31, 2006 |
|
|
|
Current U.S.
Class: |
600/1 |
Current CPC
Class: |
A61K 41/0052 20130101;
A61K 31/16 20130101; A61K 45/06 20130101; A61K 31/337 20130101;
A61K 31/337 20130101; A61P 35/00 20180101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 31/16 20130101; A61K 31/165 20130101; A61P 35/02
20180101; A61K 31/165 20130101; A61K 41/0052 20130101; A61P 43/00
20180101; A61P 35/04 20180101 |
Class at
Publication: |
600/1 |
International
Class: |
A61M 36/00 20060101
A61M036/00 |
Claims
1-20. (canceled)
21. A method of treating a subject with cancer, said method
comprising administering to the subject an effective amount of a
compound of represented by the following Structural Formula:
##STR00043## or a tautomer, pharmaceutically acceptable salt,
solvate, clathrate, or prodrug thereof, wherein: Y is a covalent
bond or an optionally substituted straight chained hydrocarbyl
group, or, Y, taken together with both >C.dbd.Z groups to which
it is bonded, is an optionally substituted aromatic group;
R.sub.1-R.sub.4 are independently --H, an optionally substituted
aliphatic group, an optionally substituted aryl group, or R.sub.1
and R.sub.3 taken together with the carbon and nitrogen atoms to
which they are bonded, and/or R.sub.2 and R.sub.4 taken together
with the carbon and nitrogen atoms to which they are bonded, form a
non-aromatic heterocyclic ring optionally fused to an aromatic
ring; R.sub.7-R.sub.8 are independently --H, an optionally
substituted aliphatic group, or an optionally substituted aryl
group; Z is O or S; in combination with radiotherapy.
22. (canceled)
23. The method of claim 21, wherein the cancer is selected from the
group consisting of i) human sarcoma or carcinoma, selected from
the group consisting of fibrosarcoma, myxosarcoma, liposarcoma,
chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,
endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,
synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,
rhabdomyosarcoma, colon carcinoma, colorectal cancer, anal
carcinoma, esophageal cancer, gastric cancer, hepatocellular
cancer, bladder cancer, endometrial cancer, pancreatic cancer,
breast cancer, ovarian cancer, prostate cancer, stomach cancer,
atrial myxomas, squamous cell carcinoma, basal cell carcinoma,
adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,
thyroid and parathyroid neoplasms, papillary carcinoma, papillary
adenocarcinomas, cystadenocarcinoma, medullary carcinoma,
bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct
carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'
tumor, cervical cancer, testicular tumor, lung carcinoma, small
cell lung carcinoma, non-small-cell lung cancer, bladder carcinoma,
epithelial carcinoma, glioma, pituitary neoplasms, astrocytoma,
medulloblastoma, craniopharyngioma, ependymoma, pinealoma,
hemangioblastoma, acoustic neuroma, schwannomas, oligodendroglioma,
meningioma, spinal cord tumors, melanoma, neuroblastoma,
pheochromocytoma, Types 1-3 endocrine neoplasia and retinoblastoma;
and ii) leukemia, selected from the group consisting of acute
lymphocytic leukemia, acute myelocytic leukemia; chronic leukemia,
polycythemia vera, lymphoma, multiple myeloma, Waldenstrobm's
macroglobulinemia, heavy chain disease, T-cell leukemias, B cell
leukemia; mixed cell leukemias, myeloid leukemias, neutrophilic
leukemia, eosinophilic leukemia, monocytic leukemia, myelomonocytic
leukemia, Naegeli-type myeloid leukemia, and nonlymphocytic
leukemia.
24. The method claim 23, wherein the cancer is selected from the
group consisting of multiple myeloma, T-cell leukemia, B-cell
leukemia, promyelocytes, uterine sarcoma, monocytic leukemia,
lymphoma, renal cell carcinoma, melanoma, multiple myeloma,
myeloma, lymphoma, non-small-cell lung cancer, squamous cell
carcinoma, basal cell carcinoma, fibrosarcoma, malignant brain
tumors, Kaposi's. Sarcoma, hairy cell leukemia, ovarian cancer,
breast cancer, colorectal cancer, lung cancer, leukemia, prostate
cancer, pancreatic cancer, head and neck cancer, and liver
cancer.
25. (canceled)
26. A method of treating a subject with an immunosensitive cancer,
comprising administering to the subject an effective amount of a
compound represented by the following Structural Formula:
##STR00044## or a tautomer, pharmaceutically acceptable salt,
solvate, clathrate, or prodrug thereof, wherein: Y is a covalent
bond or an optionally substituted straight chained hydrocarbyl
group, or, Y, taken together with both >C.dbd.Z groups to which
it is bonded, is an optionally substituted aromatic group;
R.sub.1-R.sub.4 are independently --H, an optionally substituted
aliphatic group, an optionally substituted aryl group, or R.sub.1
and R.sub.3 taken together with the carbon and nitrogen atoms to
which they are bonded, and/or R.sub.2 and R.sub.4 taken together
with the carbon and nitrogen atoms to which they are bonded, form a
non-aromatic heterocyclic ring optionally fused to an aromatic
ring; R.sub.7-R.sub.8 are independently --H, an optionally
substituted aliphatic group, or an optionally substituted aryl
group; Z is O or S; and in combination with radiotherapy.
27. The method claim 26, wherein the immunosensitive cancer is
selected from the group consisting of renal cell carcinoma,
melanoma, multiple myeloma, myeloma, lymphoma, non-small-cell lung
cancer, squamous cell carcinoma, basal cell carcinoma, bladder
cancer, prostate cancer, fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia.
28. (canceled)
29. (canceled)
30. The method of claim 21, wherein Z is O, R.sub.1 and R.sub.2 are
the same and R.sub.3 and R.sub.4 are the same.
31. The method of claim 30, wherein: Y is a covalent bond,
--C(R.sub.5R.sub.6)--, --(CH.sub.2CH.sub.2)--, trans-(CH.dbd.CH)--,
cis-(CH.dbd.CH)-- or --(C.ident.C)--; and R.sub.5 and R.sub.6 are
each independently --H, an aliphatic or substituted aliphatic
group, or R.sub.5 is --H and R.sub.5 is an optionally substituted
aryl group, or, R.sub.5 and R.sub.6, taken together, are an
optionally substituted C2-C6 alkylene group.
32. The method of claim 31, wherein: Y is --C(R.sub.5R.sub.6)--;
R.sub.1 and R.sub.2 are each an optionally substituted aryl group;
and R.sub.3 and R.sub.4 are each an optionally substituted
aliphatic group.
33. The method of claim 32, wherein R.sub.5 is --H and R.sub.6 is
--H, an aliphatic or substituted aliphatic group R.sub.1 and
R.sub.2 are each an optionally substituted phenyl group; and
R.sub.3 and R.sub.4 are each an alkyl group optionally substituted
with --OH, halogen, phenyl, benzyl, pyridyl, or C1-C8 alkoxy and
R.sub.6 is --H or methyl.
34. (canceled)
35. (canceled)
36. The method of claim 33, wherein the phenyl group represented by
R.sub.1 and the phenyl group represented by R.sub.2 are optionally
substituted with one or more groups selected from: --R.sup.a, --OH,
--Br, --Cl, --I, --F, --OR.sup.a, --O--COR.sup.a, --COR.sup.a,
--CN, --NCS, --NO.sub.2, --COOH, --SO.sub.3H, --NH.sub.2,
--NHR.sup.a, --N(R.sup.aR.sup.b), --COOR.sup.a, --CHO,
--CONH.sub.2, --CONHR.sup.a, --CON(R.sup.aR.sup.b), --NHCOR.sup.a,
--NR.sup.cCOR.sup.a, --NHCONH.sub.2, --NHCONR.sup.aH,
--NHCON(R.sup.aR.sup.b), --NR.sup.cCONH.sub.2,
--NR.sup.cCONR.sup.aH, --NR.sup.cCON(R.sup.aR.sup.b),
--C(.dbd.NH)--NH.sub.2, --C(.dbd.NH)--NHR.sup.a,
--C(.dbd.NH)--N(R.sup.aR.sup.b), --C(.dbd.NR.sup.c)--NH.sub.2,
--C(.dbd.NR.sup.c)--NHR.sup.a,
--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NH--C(.dbd.NH)--NH.sub.2,
--NH--C(.dbd.NH)--NHR.sup.a, --NH--C(.dbd.NH)--N(R.sup.aR.sup.b),
--NH--C(.dbd.NR.sup.c)--NH.sub.2,
--NH--C(.dbd.NR.sup.c)--NHR.sup.a,
--NH--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b),
--NR.sup.d--C(.dbd.NH)--NH.sub.2,
--NR.sup.d--C(.dbd.NH)--NHR.sup.a,
--NR.sup.d--C(.dbd.NH)--N(R.sup.aR.sup.b),
--NR.sup.d--C(.dbd.NR.sup.c)--NH.sub.2,
--NR.sup.d--C(.dbd.NR.sup.c)--NHR.sup.a,
--NR.sup.d--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NHNH.sub.2,
--NHNHR.sup.a, --NHNHR.sup.aR.sup.b, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.a, --SO.sub.2NR.sup.aR.sup.b, --CH.dbd.CHR.sup.a,
--CH.dbd.CR.sup.aR.sup.b, --CR.sup.c.dbd.CR.sup.aR.sup.b,
--CR.sup.c.dbd.CHR.sup.a, --CR.sup.c.dbd.CR.sup.aR.sup.b,
--CCR.sup.a, --SH, --SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
wherein R.sup.a-R.sup.d are each independently an alkyl group,
aromatic group, non-aromatic heterocyclic group; or,
--N(R.sup.aR.sup.b), taken together, form an optionally substituted
non-aromatic heterocyclic group, wherein the alkyl, aromatic and
non-aromatic heterocyclic group represented by R.sup.a-R.sup.d and
the non-aromatic heterocyclic group represented by
--N(R.sup.aR.sup.b) are each optionally and independently
substituted with one or more groups represented by R.sup.#, wherein
R.sup.# is R.sup.+, --OR.sup.+, --O(haloalkyl), --SR.sup.+,
--NO.sub.2, --CN, --NCS, --N(R.sup.+).sub.2, --NHCO.sub.2R.sup.+,
--NHC(O)R.sup.+, --NHNHC(O)R.sup.+, --NHC(O)N(R.sup.+).sub.2,
--NHNHC(O)N(R.sup.+).sub.2, --NHNHCO.sub.2R.sup.+,
--C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --CO.sub.2R.sup.+,
--C(O)R.sup.+, C(O)N(R.sup.+).sub.2, --OC(O)R.sup.+,
--OC(O)N(R.sup.+).sub.2, --S(O).sub.2R.sup.+,
--SO.sub.2N(R.sup.+).sub.2, --S(O)R.sup.+,
--NHSO.sub.2N(R.sup.+).sub.2, --NHSO.sub.2R.sup.+,
--C(.dbd.S)N(R.sup.+).sub.2, or --C(.dbd.NH)--N(R.sup.+).sub.2;
wherein R.sup.+ is --H, a C1-C4 alkyl group, a monocyclic
heteroaryl group, a non-aromatic heterocyclic group or a phenyl
group optionally substituted with alkyl, haloalkyl, alkoxy,
haloalkoxy, halo, --CN, --NO.sub.2, amine, alkylamine or
dialkylamine; or --N(R.sup.+).sub.2 is a non-aromatic heterocyclic
group, provided that non-aromatic heterocyclic groups represented
by R.sup.+ and --N(R.sup.+).sub.2 that comprise a secondary ring
amine are optionally acylated or alkylated.
37. The method of claim 36, wherein the phenyl groups represented
by R.sub.1 and R.sub.2 are optionally substituted with C1-C4 alkyl,
C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, benzyl,
pyridyl, --OH, --NH.sub.2, --F, --Cl, --Br, --I, --NO.sub.2 or
--CN.
38. The method of claim 37, wherein the phenyl groups represented
by R.sub.1 and R.sub.2 are optionally substituted with --OH, --CN,
halogen, C1-4 alkyl or C1-C4 alkoxy and R.sub.3 and R.sub.4 are
each methyl or ethyl optionally substituted with --OH, halogen or
C1-C4 alkoxy.
39. The method of claim 31, wherein: Y is --CR.sub.5R.sub.6--;
R.sub.1 and R.sub.2 are both an optionally substituted aliphatic
group; R.sub.5 is --H; and R.sub.6 is --H or an optionally
substituted aliphatic group.
40. The method of claim 39, wherein R.sub.1 and R.sub.2 are both a
C3-C8 cycloalkyl group optionally substituted with at least one
alkyl group; and R.sub.3 and R.sub.4 are both an alkyl group
optionally substituted with --OH, halogen, phenyl, benzyl, pyridyl,
or C1-C8 alkoxy; and R.sub.6 is --H or methyl.
41. (canceled)
42. The method of claim 40, wherein R.sub.1 and R.sub.2 are both
cyclopropyl or 1-methylcyclopropyl.
43. The method of claim 21, wherein the compound is represented by
the following Structural Formula: ##STR00045## or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate, or prodrug
thereof, wherein: R.sub.7-R.sub.8 are both --H, and: R.sub.1 and
R.sub.2 are both phenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
phenyl, R.sub.3 and R.sub.4 are both ethyl, and R.sub.5 and R.sub.6
are both --H; R.sub.1 and R.sub.2 are both 4-cyanophenyl, R.sub.3
and R.sub.4 are both methyl, R.sub.5 is methyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 4-methoxyphenyl, R.sub.3 and R.sub.4
are both methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and
R.sub.2 are both phenyl, R.sub.3 and R.sub.4 are both methyl,
R.sub.5 is methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
phenyl, R.sub.3 and R.sub.4 are both ethyl, R.sub.5 is methyl, and
R.sub.6 is --H; R.sub.1 and R.sub.2 are both 4-cyanophenyl, R.sub.3
and R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 2,5-dimethoxyphenyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 2,5-dimethoxyphenyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is methyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 3-cyanophenyl, R.sub.3 and R.sub.4 are
both methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and
R.sub.2 are both 3-fluorophenyl, R.sub.3 and R.sub.4 are both
methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2
are both 4-chlorophenyl, R.sub.3 and R.sub.4 are both methyl,
R.sub.5 is methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
2-dimethoxyphenyl; R.sub.3 and R.sub.4 are both methyl, and R.sub.5
and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
3-methoxyphenyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5
and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,3-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,3-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, R.sub.5
is methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
2,5-difluorophenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,5-difluorophenyl, R.sub.3 and R.sub.4 are both methyl, R.sub.5 is
methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
2,5-dichlorophenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,5-dimethylphenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,5-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
phenyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,5-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, R.sub.5
is methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
cyclopropyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both cyclopropyl,
R.sub.3 and R.sub.4 are both ethyl, and R.sub.5 and R.sub.6 are
both --H; R.sub.1 and R.sub.2 are both cyclopropyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is methyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is methyl and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is ethyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is n-propyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both methyl;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both ethyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 is
methyl, R.sub.4 is ethyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 2-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 2-phenylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 1-phenylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both cyclobutyl, R.sub.3 and R.sub.4 are
both methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and
R.sub.2 are both cyclopentyl, R.sub.3 and R.sub.4 are both methyl,
and R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
cyclohexyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both cyclohexyl,
R.sub.3 and R.sub.4 are both phenyl, and R.sub.5 and R.sub.6 are
both --H; R.sub.1 and R.sub.2 are both methyl, R.sub.3 and R.sub.4
are both methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and
R.sub.2 are both methyl, R.sub.3 and R.sub.4 are both t-butyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
methyl, R.sub.3 and R.sub.4 are both phenyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both t-butyl, R.sub.3
and R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are ethyl, R.sub.3 and R.sub.4 are both methyl,
and R.sub.5 and R.sub.6 are both --H; or R.sub.1 and R.sub.2 are
both n-propyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H.
44. The method of claim 21, wherein the compound is represented by
the following Structural Formula: ##STR00046## or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate, or prodrug
thereof.
45. The method of claim 21, wherein the compound is represented by
one of the following Structural Formulas: ##STR00047## or a
tautomer, pharmaceutically acceptable salt, solvate, clathrate, or
prodrug thereof.
46. The method of claim 21, wherein the compound is represented by
the following Structural Formula: ##STR00048## or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate, or prodrug
thereof.
47. The method of claim 21, wherein the compound is a disodium or a
dipotassium salt.
48. The method of claim 21, further comprising administering to the
subject an anticancer agent.
49. (canceled)
50. The method of claim 48, wherein the microtubulin stabilizer is
a taxol or a taxol analog.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 11/897,538, filed Aug. 30, 2007. This application claims the
benefit of U.S. Provisional Application No. 60/841,570, filed Aug.
31, 2006, the entire teachings of which are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] Cancer is a group of diseases that are characterized by
uncontrolled cell division. This uncontrolled division can
compromise the function of an organism and ultimately may cause its
death.
[0003] On average, in the United States, men have a 1 in 2 lifetime
risk of developing cancer and women, a 1 in 3 risk. The
International Agency for Research on Cancer estimated that there
were 5.3 million new cases of cancer and 3.5 million cancer deaths
worldwide in 2000. In the United States, more than 1.2 million new
cases were diagnosed in 2002 and more than 550,000 people died of
the disease. In fact, cancer is the second leading cause of death
in the United States, exceeded only by heart disease.
[0004] Many cancers are immunosensitive. Immunosensitive cancers
respond to immunotherapy, i.e., agents that stimulate the immune
system. Examples of immunosensitive cancers include, renal cell
carcinoma, melanoma, multiple myeloma, myeloma, lymphoma,
non-small-cell lung cancer, bladder cancer, prostate cancer,
squamous cell carcinoma, basal cell carcinoma, fibrosarcoma,
malignant brain tumors, Kaposi's Sarcoma, chronic myelogenous
leukemia (CML) and hairy cell leukemia.
[0005] Heat shock proteins (HSPs) are found in virtually all
prokaryotic and eukaryotic cells where they support folding of
nascent polypeptides, prevent protein aggregation, and assist
transport of other proteins across membranes. The proteins in the
Hsp70 family (referred to collectively as "Hsp70") play a dual role
of protecting cells from lethal damage after environmental stress,
on the one hand, and targeting cells for immune mediated cytolytic
attack on the other hand. Increased expression of Hsp70 in the
cytoplasma is known to protect a broad range of cells under stress
by preventing the misfolding, aggregation and denaturation of
cytoplasmic proteins and inhibiting various apoptotic pathways
(Mosser, et al., Mol Cell Biol. 2000 October; 20(19): 7146-7159;
Yenari, Adv Exp Med Biol, 2002, 513, 281-299; Kiang and Tsokos,
Pharmacol Ther. 1998; 80(2):182-201). However, membrane-bound Hsp70
provides a target structure for cytolytic attack mediated by
natural killer cells.
[0006] Cells can experience stress due to temperature; injury
(trauma); genetic disease; metabolic defects; apoptosis; infection;
toxins; radiation; oxidants; excess/lack of nutrients or metabolic
products; and the like. For example, it is known in the art that
cells damaged in the following variety of medical conditions can
experience a protective effect in response to Hsp70.
[0007] Protein misfolding/aggregation conditions resulting in
neurodegeneration include Alzheimers' disease (Zhang, et al., J.
Neuroscience, 2004, 24(23), 5315-5321; Klettner, Drug News
Perspect, 2004 17(5), 299-306); Huntington's disease (Klettner,
ibid); Parkinson's disease (Auluck, et al., Science, 2002,
295(5556), 865-868); and the like. Other neurodegenerative
conditions include spinal/bulbar muscular atrophy (Sobue, Nihon
Shinkei Seishin Yakurigaku Zasshi, 2001, 21(1), 21-25); and
familial amyotrophic lateral sclerosis (Howland, et al., Proc Nat
Acad Sci USA, 2002, 99(3), 1604-1609; Sobue, ibid; Vleminck, et
al., J Neuropathol Exp Neurol, 2002, 61(11), 968-974).
[0008] Ischemia and associated oxidative damage affects diverse
tissues including: neurons and glia (Carmel, et al., Exp Neurol,
2004, 185(1) 81-96; Renshaw and Warburton, Front Biosci, 2004, 9,
110-116; Yenari, Adv Exp Med Biol, 2002, 513, 281-299; Kelly and
Yenari, Curr Res Med Opin, 2002, 18 Suppl 2, s55-60; Lee, et al.,
Exp Neurol, 2001, 170(1), 129-139; Klettner, ibid; Klettner and
Herdegen, Br J Pharmacol, 2003, 138(5), 1004-1012); cardiac muscle
(Marber, M. S., et al. (1995) J. Clin. Invest. 95:1446-1456;
Plumier, J. C., et al. (1995) J. Clin. Invest. 95:1854-1860;
Radford, N. B., et al. (1996) Proc. Natl. Acad. Sci. USA 93(6):
2339-2342; Voss, et al., Am J Physiol Heart Circ Physiol 285:
H687-H692, 2003); liver tissue (Doi, et al.,
Hepatogastroenterology. 2001 March-April; 48(38):533-40; Gao, et
al. World J Gastroenterol 2004; 10(7):1019-1027); skeletal muscle
(Lepore et al., Cell Stress & Chaperones, 2001, 6(2), 93-96);
kidney tissue (Chen, et al., Kidney Int. 1999; 56: 1270-1273; Beck,
et al., Am J Physiol Renal Physiol 279: F203-F215, 2000.);
pulmonary tissue (Hiratsuka, et al., J Heart Lung Transplant. 1998
December; 17(12):1238-46); pancreatic tissue (Bellmann, et al., J
Clin Invest. 1995 June; 95(6): 2840-2845), and the like.
[0009] Seizure conditions that damage neurons include, e.g.,
epileptic seizure (Yenari, ibid; Blondeau, et al. Neuroscience
2002, 109(2), 231-241); or chemically induced seizure (Tsuchiya, et
al., Neurosurgery, 2003, 53(5), 1179-1187).
[0010] Thermal stresses include hyperthermia conditions such as
fever, heat stroke, and the like (Barclay and Robertson, J
Neurobiol, 2003 56(4), 360-271; Sato, et al., Brain Res, 1996,
740(1-2), 117-123); and hypothermia (Kandor and Goldberg, Proc Natl
Acad Sci USA. 1997 May 13; 94(10): 4978-4981).
[0011] Aging includes conditions such as atherosclerosis which
affects smooth muscle cells (Minowada, G. and Welch, W. J. (1995)
J. Clin. Invest. 95:3-12; Johnson, A. J., et al. (1995) Arterio.
Thromb. Vasc. Biol. 15(1):27-36).
[0012] Other conditions include radiation damage, e.g., from
ultraviolet light to tissues such as murine fibroblasts (Simon, M.
M., et al. (1995) J. Clin. Res. 95(3): 926-933), and light damage
to retinal cells (Yu, et, al, Molecular Vision 2001; 7:48-56).
[0013] Trauma includes, for example, mechanical injury, e.g.,
pressure damage to retinal ganglions in glaucoma (Ishii, et al.,
Invest Opthalmol V is Sci, 2003, 44(5), 1982-1992).
[0014] Toxic conditions include doses of chemicals or biochemicals,
for example, methamphetamine (Malberg & Seiden, Poster "MDMA
Administration Induces Expression of HSP70 in the Rat Brain"
Society for Neuroscience Annual Meeting, New Orleans, La., Oct.
25-30, 1997); antiretroviral HIV therapeutics (Keswani, et al.,
Annals Neurology, 2002, 53(1), 57-64); heavy metals, amino acid
analogs, chemical oxidants, ethanol, glutamate, and other toxins
(Ashburner, M. and Bonner, J. J. (1979) Cell: 17:241-254;
Lindquist, S. (1986) Ann. Rev. Biochem. 55:1151-1191; Crag, E A.
(1985) Grit. Rev. Biochem. 18(3):239-280; Morimoto, et al., In: The
Biology of Heat Shock Proteins and Molecular Chaperone, (1994) pp.
417-455. Cold Spring Harbor Laboratory Press. Cold Spring Harbor,
N.Y.); and the like.
[0015] Therefore, there is a need for new methods of increasing
expression of Hsp70 in order to treat disorders responsive to
Hsp70.
[0016] Extracellular Hsp70 and membrane bound Hsp70 have been shown
to play key roles in activation of the innate immune system.
Monocytes have been shown to secrete proinflammatory cytokines in
response to soluble Hsp70 protein and membrane bound Hsp70 has been
shown to provide a target structure for cytolytic attack by natural
killer cell.
[0017] Natural killer (NK) cells, a type of white blood cell, are
known to be an important component of the body's immune system.
Because the defining function of NK cells is spontaneous
cytotoxicity without prior immunization, NK cells can be the first
line of defense in the immune system, and are believed to play a
role in attacking cancer cells and infectious diseases. Many
conditions, such as immunodeficiency diseases, aging, toxin
exposure, endometriosis, and the like can leave subjects with
lowered NK cell activity or dysfunctional NK cells.
[0018] For example, subjects can have decreased or deficient NK
cell activity, in conditions such as chronic fatigue syndrome
(chronic fatigue immune dysfunction syndrome) or Epstein-Barr
virus, post viral fatigue syndrome, post-transplantation syndrome
or host-graft disease, exposure to drugs such as anticancer agents
or nitric oxide synthase inhibitors, natural aging, and various
immunodeficiency conditions such as severe combined
immunodeficiency, variable immunodeficiency syndrome, and the like.
(Caligiuri M, Murray C, Buchwald D, Levine H, Cheney P, Peterson D,
Komaroff A L, Ritz J. Phenotypic and functional deficiency of
natural killer cells in patients with chronic fatigue syndrome.
Journal of Immunology 1987; 139: 3306-13; Morrison L J A, Behan W H
M, Behan P O. Changes in natural killer cell phenotype in patients
with post-viral fatigue syndrome. Clinical and Experimental
Immunology 1991; 83: 441-6; Klingemann, H G Relevance and Potential
of Natural Killer Cells in Stem Cell Transplantation Biology of
Blood and Marrow Transplantation 2000; 6:90-99; Ruggeri L, Capanni
M, Mancusi A, Aversa F, Martelli M F, Velardi A. Natural killer
cells as a therapeutic tool in mismatched transplantation. Best
Pract Res Clin Haematol. 2004 September; 17(3):427-38; Cifone M G,
Ulisse S, Santoni A. Natural killer cells and nitric oxide. Int
Immunopharmacol. 2001 August; 1(8):1513-24; Plackett T P, Boehmer E
D, Faunce D E, Kovacs E J. Aging and innate immune cells. J Leukoc
Biol. 2004 August; 76(2):291-9. Epub 2004 Mar. 23; Alpdogan O, van
den Brink M R. IL-7 and IL-15: therapeutic cytokines for
immunodeficiency. Trends Immunol. 2005 January; 26(1):56-64; Heusel
J W, Ballas Z K. Natural killer cells: emerging concepts in
immunity to infection and implications for assessment of
immunodeficiency. Curr Opin Pediatr. 2003 December; 15(6):586-93;
Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M. Gene therapy of
X-linked severe combined immunodeficiency. Int J Hematol. 2002
November; 76(4):295-8; Baumert E, Schlesier M, Wolff-Vorbeck G,
Peter H H. Alterations in lymphocyte subsets in variable
immunodeficiency syndrome Immun Infekt. 1992 July; 20(3):73-5.)
[0019] NK cells are known to have activity against a wide range of
infectious pathogens such as bacteria, viruses, fungi, protozoan
parasites, combined infections, e.g., combined bacterial/viral
infections, and the like. NK cells are believed to be particularly
important in combating intracellular infections where the pathogens
replicate in the subjects cells, e.g., a substantial fraction of
viruses and many other pathogens that can form intracellular
infections.
[0020] For example, a wide range of fungal infections are reported
to be targeted by NK cells such as Cryptococcus neoformans,
dermatophytes, e.g., Trichophyton rubrum, Candida albicans,
Coccidioides immitis, Paracoccidioides brasiliensis, or the like
(Hidore M R, Mislan T W, Murphy J W. Responses of murine natural
killer cells to binding of the fungal target Cryptococcus
neoformans Infect Immun. 1991 April; 59(4):1489-99; Akiba H, Motoki
Y, Satoh M, Iwatsuki K, Kaneko F; Recalcitrant trichophytic
granuloma associated with NK-cell deficiency in a SLE patient
treated with corticosteroid. Eur J. Dermatol. 2001
January-February; 11(1):58-62; Mathews H L, Witek-Janusek L.
Antifungal activity of interleukin-2-activated natural killer
(NK1.1+) lymphocytes against Candida albicans. J Med. Microbiol.
1998 November; 47(11):1007-14; Ampel N M, Bejarano G C, Galgiani J
N. Killing of Coccidioides immitis by human peripheral blood
mononuclear cells. Infect Immun. 1992 October; 60(10):4200-4;
Jimenez B E, Murphy J W. In vitro effects of natural killer cells
against Paracoccidioides brasiliensis yeast phase. Infect Immun.
1984 November; 46(2):552-8.)
[0021] Also targeted by NK cells are bacteria, especially
intracellular bacteria, e.g., Mycobacterium tuberculosis,
Mycobacterium avium, Listeria monocytogenes, many different
viruses, such as human immunodeficiency virus, herpesviruses,
hepatitis, and the like, and viral/bacterial co-infection (Esin S,
Batoni G, Kallenius G, Gaines H, Campa M, Svenson S B, Andersson R,
Wigzell H. Proliferation of distinct human T cell subsets in
response to live, killed or soluble extracts of Mycobacterium
tuberculosis and Myco. avium. Clin Exp Immunol. 1996 June;
104(3):419-25; Kaufmann S H. Immunity to intracellular bacteria.
Annu Rev Immunol. 1993; 11:129-63; See D M, Khemka P, Sahl L, Bui
T, Tilles J G. The role of natural killer cells in viral
infections. Scand J. Immunol. 1997 September; 46(3):217-24; Brenner
B G, Dascal A, Margolese R G, Wainberg M A. Natural killer cell
function in patients with acquired immunodeficiency syndrome and
related diseases. J Leukoc Biol. 1989 July; 46(1):75-83; Kottilil
S, Natural killer cells in HIV-1 infection: role of NK
cell-mediated non-cytolytic mechanisms in pathogenesis of HIV-1
infection. Indian J Exp Biol. 2003 November; 41(11):1219-25; Herman
R B, Koziel M J. Natural killer cells and hepatitis C: is losing
inhibition the key to clearance? Clin Gastroenterol Hepatol. 2004
December; 2(12):1061-3; Beadling C, Slifka M K. How do viral
infections predispose patients to bacterial infections? Curr Opin
Infect Dis. 2004 June; 17(3):185-91)
[0022] In addition, NK cells combat protozoal infections including
toxoplasmosis, trypanosomiasis, leishmaniasis and malaria,
especially intracellular infections (Korbel D S, Finney O C, Riley
E M. Natural killer cells and innate immunity to protozoan
pathogens. Int J Parasitol. 2004 December; 34(13-14):1517-28; Ahmed
J S, Mehlhorn H. Review: the cellular basis of the immunity to and
immunopathogenesis of tropical theileriosis. Parasitol Res. 1999
July; 85(7):539-49; Osman M, Lausten S B, El-Sefi T, Boghdadi I,
Rashed M Y, Jensen S L. Biliary parasites. Dig Surg. 1998;
15(4):287-96; Gazzinelli R T, Denkers E Y, Sher A. Host resistance
to Toxoplasma gondii: model for studying the selective induction of
cell-mediated immunity by intracellular parasites. Infect Agents
Dis. 1993 June; 2(3):139-49; Askonas B A, Bancroft G J. Interaction
of African trypanosomes with the immune system. Philos Trans R Soc
Lond B Biol Sci. 1984 Nov. 13; 307(1131):41-9; Allison A C, Eugui E
M. The role of cell-mediated immune responses in resistance to
malaria, with special reference to oxidant stress. Annu Rev
Immunol. 1983; 1:361-92.)
[0023] NK cells have been shown to play a role in attacking cancer
cells that present membrane bound Hsp70. It is believed that
membrane bound Hsp70 binds to CD94 receptors on the surface of NK
cells and cause them to produce and secrete high amounts of the
enzyme, granzyme B which is thought to enter the tumor cell via
interaction with membrane bound Hsp70 and induce apoptosis (see
Radons and Multhoff, Exerc. Immunol. Rev. (2005), 11:17-33).
Therefore, there is an urgent need for effective treatments for
increasing NK cell activity for the treatment of cancer and other
disorders that respond to NK induction.
[0024] Radiation therapy and chemotherapy are commonly used
treatments for cancer. However, it is well known that these
therapies often result in incomplete killing of the cancer cells
and that reoccurrence of the cancer can result in cancer that is
more resistant to radiation or chemotherapy.
[0025] Many chemotherapeutic drugs cause cells to generate reactive
oxygen species (ROS) which can lead to cellular signaling that
induces either apoptosis or proliferation. ROS are generated during
normal metabolism in the mitochondria of cells. However, the
buffering action of endogenous thiols, such as glutathione and
thioredoxin, protect cells from oxidative damage and help maintain
the reduction-oxidation (redox) state of the cell. If ROS are
elevated to a level which exceeds the buffering capacity of the
cell, activation of signaling pathways and gene expression that
induce apoptosis can occur. Cancer cells are generally more
susceptible to ROS induced apoptosis than normal cells because the
environment created by uncontrolled growth of a tumor is typically
hypoxic. However, radiation therapy and chemotherapy that results
in incomplete killing of cancer cells can result in the remaining
cancer cells developing a resistance to oxidative stress. For
example, cancer cells can compensate for the generation of ROS by
upregulating the amount of glutathione (GSH) or components of the
thioredoxin system, such as thioredoxin reductase. GSH is a
cellular antioxidant that contains a reducing thiol group which
donates electrons to ROS, thereby neutralize them. The thioredoxin
system includes thioredoxin, a protein that has a redox-active
disulfide group which can be reduced by thioredoxin reductase to
two dithiol groups in the presence of NADPH. The dithiol form of
thioredoxin is a powerful protein-disulfide reductase which helps
regulate the redox state of the cell. Cellular resistance to
anticancer drugs such as paclitaxel has been shown to be
proportional to the total antioxidant capacity of a target
cell.
[0026] By upregulating cellular defense mechanisms against ROS,
cancer cells can evade destruction by radiation and
chemotherapeutic drugs. Therefore, a need exists for agents that
reduce cellular mechanism of compensating for ROS and induce
cellular signaling pathways that lead to apoptosis. Such agents
would be expected to increase the effectiveness of existing
anti-cancer agents.
SUMMARY OF THE INVENTION
[0027] Certain compounds of the invention induce Hsp70 production
in cells and thereby increase the level of Hsp70 in the cytoplasm
and on the surface of cells. In addition, certain compounds of the
invention are cytotoxic to cancer cell lines, including multi-drug
resistant cancer cell lines, and enhance the anti-proliferative and
apoptotic activity (e.g., anti-cancer activity) of Taxol and taxane
analogs.
[0028] It has now been found that bis(thiohydrazide amides) in
combination with taxol significantly increase the time to disease
progression in patients with Stage 1V melanoma. As noted above
melanoma is an immunosensitive cancer. The use of bis(thiohydrazide
amides) in combination with other anticancer therapies to treat a
proliferative disorder, such as cancer, is disclosed herein. In one
embodiment, the method is used to treat melanoma and other
immunosensitive cancers.
[0029] Moreover it has also been found that bis(thiohydrazide
amides) concentrate in the kidneys. In one particular embodiment,
the method of treating renal cell carcinoma, another
immunosensitive cancer, is also disclosed herein.
[0030] The present invention is directed to methods of treating a
subject with a proliferative disorder, such as cancer, comprising
administering to the subject an effective amount of a
bis(thiohydrazide amide) in combination with hyperthermia
treatment, optionally comprising one or more additional anticancer
therapies.
[0031] The present invention is also directed to methods of
treating a subject with a proliferative disorder, such as cancer,
comprising administering to the subject an effective amount of a
bis(thiohydrazide amide) in combination with radiotherapy,
optionally comprising one or more additional anticancer
therapies.
[0032] The methods include administering to the subject an
effective amount of a bis(thio-hydrazide amide) represented by
Structural Formula I:
##STR00001##
[0033] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, wherein
[0034] Y is a covalent bond or an optionally substituted straight
chained hydrocarbyl group, or, Y, taken together with both
>C.dbd.Z groups to which it is bonded, is an optionally
substituted aromatic group.
[0035] R.sub.1-R.sub.4 are independently --H, an optionally
substituted aliphatic group, an optionally substituted aryl group,
or R.sub.1 and R.sub.3 taken together with the carbon and nitrogen
atoms to which they are bonded, and/or R.sub.2 and R.sub.4 taken
together with the carbon and nitrogen atoms to which they are
bonded, form a non-aromatic ring optionally fused to an aromatic
ring.
[0036] R.sub.7-R.sub.8 are independently --H, an optionally
substituted aliphatic group, or an optionally substituted aryl
group.
[0037] Z is O or S;
[0038] in combination with hyperthermia treatment or
radiotherapy.
[0039] Also disclosed are methods of treating a subject with a
cancer selected from the group consisting of: [0040] i) human
sarcoma or carcinoma, selected from the group consisting of
fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic
sarcoma, chordoma, angiosarcoma, endotheliosarcoma,
lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma,
mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma,
colon carcinoma, colorectal cancer, anal carcinoma, esophageal
cancer, gastric cancer, hepatocellular cancer, bladder cancer,
endometrial cancer, pancreatic cancer, breast cancer, ovarian
cancer, prostate cancer, stomach cancer, atrial myxomas, squamous
cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland
carcinoma, sebaceous gland carcinoma, thyroid and parathyroid
neoplasms, papillary carcinoma, papillary adenocarcinomas,
cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma,
renal cell carcinoma, hepatoma, bile duct carcinoma,
choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor,
cervical cancer, testicular tumor, lung carcinoma, small cell lung
carcinoma, non-small-cell lung cancer, bladder carcinoma,
epithelial carcinoma, glioma, pituitary neoplasms, astrocytoma,
medulloblastoma, craniopharyngioma, ependymoma, pinealoma,
hemangioblastoma, acoustic neuroma, schwannomas, oligodendroglioma,
meningioma, spinal cord tumors, melanoma, neuroblastoma,
pheochromocytoma, Types 1-3 endocrine neoplasia, retinoblastoma;
and [0041] ii) leukemia, selected from the group consisting of
acute lymphocytic leukemia, acute myelocytic leukemia; chronic
leukemia, polycythemia vera, lymphoma, multiple myeloma,
Waldenstrobm's macroglobulinemia, heavy chain disease, T-cell
leukemias, B cell leukemia; mixed cell leukemias, myeloid
leukemias, neutrophilic leukemia, eosinophilic leukemia, monocytic
leukemia, myelomonocytic leukemia, Naegeli-type myeloid leukemia,
and nonlymphocytic leukemia; comprising administering to the
subject an effective amount of a compound represented by Structural
Formula I and in combination with hyperthermia treatment or
radiotherapy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1 is a Kaplan-Meier graph of time-to-progression
(resumption of cancer growth) in a study of Paclitaxel+compound (1)
versus Paclitaxel alone.
[0043] FIG. 2 is a graph of the tissue distribution of compound (1)
and compound (18).
[0044] FIG. 3 is a graph showing that Ramos cells treated with
Compound 1 emit more reactive oxygen species than cells treated
with DMSO alone. The production of reactive oxygen species by the
cells was measured using a cell permeable DCF-DA probe which, when
oxidized by reactive oxygen species, emits a green fluorescence
that was detected by flow cytometry.
[0045] FIG. 4 is a graph showing that induction of reactive oxygen
species by Compound 1 can be blocked by treating Ramos cells with
NAC in combination with Compound 1. The production of reactive
oxygen species was measured using a DCF-DA probe and detected using
flow cytometry.
[0046] FIG. 5 is a graph showing that Compound 1 induced the
production of reactive oxygen species in Ramos cells in a time
dependent manner. The production of reactive oxygen species was
measured using a DCF-DA probe and detected using flow
cytometry.
[0047] FIG. 6 is a graph showing both Tiron and NAC block the
production of reactive oxygen species induced by treatment of cells
with Compound 1. Tiron and NAC are antioxidants that function by
different mechanisms. The production of reactive oxygen species was
measured using a DCF-DA probe and detected using flow
cytometry.
[0048] FIG. 7 is a graph showing Tiron blocks the induction of
Hsp70 by Compound 1.
[0049] FIG. 8 shows the results of a Nude mouse xenograft study to
determine the effect of Compound 1 on the in vivo growth rate of
RERF-LC-AI.sup.IVP human lung tumor cells when dosed in combination
with fractionated ionizing radiation. Tumor-bearing animals (8
mice/group) were i.v. injected 5 times per week for a total of 15
doses (closed arrowheads) with 10 mL/kg of 10/18 DRD vehicle with
or without 100 mg/kg Compound 1. Animals were also irradiated 3
times per week for a total of 9 doses (open arrowheads) with 0.5 Gy
radiation. In the combination treatment group, animals were
irradiated 420 min prior to being dosed with Compound 1. Each group
that was not dosed with Compound 1 was instead dosed with 10/18 DRD
vehicle as a mock treatment. Each group that was not irradiated was
instead anesthetized and restrained as a mock irradiation. Average
tumor volumes for each group were determined every 3-4 days (error
bars represent + or -0.5 SEM; error bars not shown the vehicle
group for clarity). Treatment with a combination of 0.5 Gy
radiation, delivered three times per week, in combination with 100
mg/kg Compound 1, dosed five times per week, substantially
inhibited tumor growth in relative to that achieved by either
single therapy alone. % T/C values are indicated on the right.
DETAILED DESCRIPTION OF THE INVENTION
[0050] The present invention relates to methods of treating a
subject with a proliferative disorder, such as cancer, comprising
administering to the subject an effective amount of a
bis(thio-hydrazide amide) represented by a formula selected from
Structural Formulas (I)-(IX) (or a compound encompassed by these
structural formulas) or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or prodrug thereof, in combination with
another anti-proliferative or anticancer therapy.
[0051] The present invention also relates to methods of treating a
subject with a proliferative disorder, such as cancer, comprising
administering to the subject an effective amount of a
bis(thio-hydrazide amide) represented by a formula selected from
Structural Formulas (I)-(IX) (or a compound encompassed by these
structural formulas) or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or prodrug thereof, in combination with
hyperthermia treatment.
[0052] The present invention also relates to methods of treating a
subject with a proliferative disorder, such as cancer, comprising
administering to the subject an effective amount of a
bis(thio-hydrazide amide) represented by a formula selected from
Structural Formulas (I)-(IX) (or a compound encompassed by these
structural formulas) or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or prodrug thereof, in combination with
radiotherapy.
[0053] The present invention is also directed to methods of
treating an immunosensitive cancer with an effective amount of a
bis(thio-hydrazide amide) represented by a formula selected from
Structural Formulas (I)-(IX) (or a compound encompassed by these
structural formulas) or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or prodrug thereof, in combination with
hyperthermia treatment. In particular, melanoma and renal cell
carcinoma are two immunosensitive treated using the disclosed
methods.
[0054] The present invention is also directed to methods of
treating an immunosensitive cancer with an effective amount of a
bis(thio-hydrazide amide) represented by a formula selected from
Structural Formulas (I)-(IX) (or a compound encompassed by these
structural formulas) or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or prodrug thereof, in combination with
radiotherapy. In particular, melanoma and renal cell carcinoma are
two immunosensitive cancers treated using the disclosed
methods.
[0055] The present invention is also directed to methods of
preventing or delaying the recurrence of an immunosensitive cancer
in a subject who has been treated for the cancer. The methods
include administering to the subject an effective amount of a
bis(thio-hydrazide amide) represented by Structural Formula I or a
tautomer, pharmaceutically acceptable salt, solvate, clathrate, or
prodrug thereof, in combination with another anti-proliferative or
anticancer therapy.
[0056] The bis(thio-hydrazide amides) employed in the disclosed
invention are represented by Structural Formula I and
pharmaceutically acceptable salts and solvates of the compounds
represented by Structural Formula I.
[0057] In one embodiment, Y in Structural Formula I is a covalent
bond, --C(R.sub.5R.sub.6)--, --(CH.sub.2CH.sub.2)--,
trans-(CH.dbd.CH)--, cis-(CH.dbd.CH)-- or --(C.ident.C)-- group,
preferably --C(R.sub.5R.sub.6)--. R.sub.1-R.sub.4 are as described
above for Structural Formula I. R.sub.5 and R.sub.6 are each
independently --H, an aliphatic or substituted aliphatic group, or
R.sub.5 is --H and R.sub.6 is an optionally substituted aryl group,
or, R.sub.5 and R.sub.6, taken together, are an optionally
substituted C2-C6 alkylene group. In one embodiment, the compound
of Structural Formula I is in the form of a pharmaceutically
acceptable salt. In one embodiment, the compound of Structural
Formula I is in the form of a pharmaceutically acceptable salt in
combination with one or more pharmaceutically acceptable cations.
The pharmaceutically acceptable cations are as described in detail
below.
[0058] In specific embodiments, Y taken together with both
>C.dbd.Z groups to which it is bonded, is an optionally
substituted aromatic group. In this instance, certain
bis(thio-hydrazide amides) are represented by Structural Formula
II:
##STR00002##
[0059] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, wherein Ring A is substituted or
unsubstituted and V is --CH-- or --N--. The other variables in
Structural Formula II are as described herein for Structural
Formula I or IIIa.
[0060] In particular embodiments, the bis(thio-hydrazide amides)
are represented by Structural Formula IIIa:
##STR00003##
[0061] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, wherein
[0062] R.sub.1-R.sub.8 are as described above for Structural
Formula I.
[0063] In Structural Formulas I-IIIa, R.sub.1 and R.sub.2 are the
same or different and/or R.sub.3 and R.sub.4 are the same or
different; preferably, R.sub.1 and R.sub.2 are the same and R.sub.3
and R.sub.4 are the same. In Structural Formulas I and IIIa, Z is
preferably O. Typically in Structural Formulas I and IIIa, Z is O;
R.sub.1 and R.sub.2 are the same; and R.sub.3 and R.sub.4 are the
same. More preferably, Z is O; R.sub.1 and R.sub.2 are the same;
R.sub.3 and R.sub.4 are the same, and R.sub.7 and R.sub.8 are the
same.
[0064] In other embodiments, the bis(thio-hydrazide amides) are
represented by Structural Formula IIIa: R.sub.1 and R.sub.2 are
each an optionally substituted aryl group, preferably an optionally
substituted phenyl group; R.sub.3 and R.sub.4 are each an
optionally substituted aliphatic group, preferably an alkyl group
optionally substituted with --OH, halogen, phenyl, benzyl, pyridyl,
or C1-C8 alkoxy and R.sub.6 is --H or methyl, more preferably,
methyl or ethyl group optionally substituted with --OH, halogen,
phenyl, benzyl, pyridyl, or C1-C8 alkoxy and R.sub.6 is --H or
methyl optionally substituted with --OH, halogen or C1-C4 alkoxy;
and R.sub.5 and R.sub.6 are as described above, but R.sub.5 is
preferably --H and R.sub.6 is preferably --H, an aliphatic or
substituted aliphatic group.
[0065] Alternatively, R.sub.1 and R.sub.2 are each an optionally
substituted aryl group; R.sub.3 and R.sub.4 are each an optionally
substituted aliphatic group; R.sub.5 is --H; and R.sub.6 is --H, an
aliphatic or substituted aliphatic group. Preferably, R.sub.1 and
R.sub.2 are each an optionally substituted aryl group; R.sub.3 and
R.sub.4 are each an alkyl group optionally substituted with --OH,
halogen, phenyl, benzyl, pyridyl, or C.sub.1-C.sub.8 alkoxy and
R.sub.6 is --H or methyl; and R.sub.5 is --H and R.sub.6 is --H or
methyl. Even more preferably, R.sub.1 and R.sub.2 are each an
optionally substituted phenyl group, preferably optionally
substituted with --OH, halogen, C1-4 alkyl or C1-C4 alkoxy; R.sub.3
and R.sub.4 are each methyl or ethyl optionally substituted with
--OH, halogen or C1-C4 alkoxy; and R.sub.5 is --H and R.sub.6 is
--H or methyl. Suitable substituents for an aryl group represented
by R.sub.1 and R.sub.2 and an aliphatic group represented by
R.sub.3, R.sub.4 and R.sub.6 are as described below for aryl and
aliphatic groups.
[0066] In another embodiment, the bis(thio-hydrazide amides) are
represented by Structural Formula IIIa: R.sub.1 and R.sub.2 are
each an optionally substituted aliphatic group, preferably a C3-C8
cycloalkyl group optionally substituted with at least one alkyl
group, more preferably cyclopropyl or 1-methylcyclopropyl; R.sub.3
and R.sub.4 are as described above for Structural Formula I,
preferably both an optionally substituted alkyl group; and R.sub.5
and R.sub.6 are as described above, but R.sub.5 is preferably --H
and R.sub.6 is preferably --H, an aliphatic or substituted
aliphatic group, more preferably --H or methyl.
[0067] Alternatively, the bis(thio-hydrazide amides) are
represented by Structural Formula IIIa: R.sub.1 and R.sub.2 are
each an optionally substituted aliphatic group; R.sub.3 and R.sub.4
are as described above for Structural Formula I, preferably both an
optionally substituted alkyl group; and R.sub.5 is --H and R.sub.6
is --H or an optionally substituted aliphatic group. Preferably,
R.sub.1 and R.sub.2 are both a C3-C8 cycloalkyl group optionally
substituted with at least one alkyl group; R.sub.3 and R.sub.4 are
both as described above for Structural Formula I, preferably an
alkyl group; and R.sub.5 is --H and R.sub.6 is --H or an aliphatic
or substituted aliphatic group. More preferably, R.sub.1 and
R.sub.2 are both a C3-C8 cycloalkyl group optionally substituted
with at least one alkyl group; R.sub.3 and R.sub.4 are both an
alkyl group group optionally substituted with --OH, halogen,
phenyl, benzyl, pyridyl, or C.sub.1-C.sub.8 alkoxy and R.sub.6 is
--H or methyl; and R.sub.5 is --H and R.sub.6 is --H or methyl.
Even more preferably, R.sub.1 and R.sub.2 are both cyclopropyl or
1-methylcyclopropyl; R.sub.3 and R.sub.4 are both an alkyl group,
preferably methyl or ethyl optionally substituted with --OH,
halogen or C1-C4 alkoxy; and R.sub.5 is --H and R.sub.6 is --H or
methyl.
[0068] In particular embodiments, the bis(thio-hydrazide amides)
are represented by Structural Formula IIIb:
##STR00004##
[0069] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, wherein
[0070] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, and Z
are as defined above for Structural Formula IIIa.
[0071] In specific embodiments, the bis(thio-hydrazide amides) are
represented by Structural Formula IVa:
##STR00005##
[0072] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, wherein: R.sub.1 and R.sub.2 are
both phenyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both phenyl, R.sub.3
and R.sub.4 are both ethyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 4-cyanophenyl, R.sub.3 and R.sub.4 are
both methyl, R.sub.5 is methyl, and R.sub.6 is --H; R.sub.1 and
R.sub.2 are both 4-methoxyphenyl, R.sub.3 and R.sub.4 are both
methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2
are both phenyl, R.sub.3 and R.sub.4 are both methyl, R.sub.5 is
methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both phenyl,
R.sub.3 and R.sub.4 are both ethyl, R.sub.5 is methyl, and R.sub.6
is --H; R.sub.1 and R.sub.2 are both 4-cyanophenyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 2,5-dimethoxyphenyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 2,5-dimethoxyphenyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is methyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 3-cyanophenyl, R.sub.3 and R.sub.4 are
both methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and
R.sub.2 are both 3-fluorophenyl, R.sub.3 and R.sub.4 are both
methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2
are both 4-chlorophenyl, R.sub.3 and R.sub.4 are both methyl,
R.sub.5 is methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
2-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5
and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
3-methoxyphenyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5
and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,3-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,3-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, R.sub.5
is methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
2,5-difluorophenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,5-difluorophenyl, R.sub.3 and R.sub.4 are both methyl, R.sub.5 is
methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
2,5-dichlorophenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,5-dimethylphenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,5-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
phenyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
2,5-dimethoxyphenyl, R.sub.3 and R.sub.4 are both methyl, R.sub.5
is methyl, and R.sub.6 is --H; R.sub.1 and R.sub.2 are both
cyclopropyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both cyclopropyl,
R.sub.3 and R.sub.4 are both ethyl, and R.sub.5 and R.sub.6 are
both --H; R.sub.1 and R.sub.2 are both cyclopropyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is methyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is methyl and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is ethyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, R.sub.5 is n-propyl, and R.sub.6 is --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both methyl;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 and
R.sub.4 are both ethyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 1-methylcyclopropyl, R.sub.3 is
methyl, R.sub.4 is ethyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 2-methylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 2-phenylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both 1-phenylcyclopropyl, R.sub.3 and
R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are both cyclobutyl, R.sub.3 and R.sub.4 are
both methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and
R.sub.2 are both cyclopentyl, R.sub.3 and R.sub.4 are both methyl,
and R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
cyclohexyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both cyclohexyl,
R.sub.3 and R.sub.4 are both phenyl, and R.sub.5 and R.sub.6 are
both --H; R.sub.1 and R.sub.2 are both methyl, R.sub.3 and R.sub.4
are both methyl, and R.sub.5 and R.sub.6 are both --H; R.sub.1 and
R.sub.2 are both methyl, R.sub.3 and R.sub.4 are both t-butyl, and
R.sub.5 and R.sub.6 are both --H; R.sub.1 and R.sub.2 are both
methyl, R.sub.3 and R.sub.4 are both phenyl, and R.sub.5 and
R.sub.6 are both --H; R.sub.1 and R.sub.2 are both t-butyl, R.sub.3
and R.sub.4 are both methyl, and R.sub.5 and R.sub.6 are both --H;
R.sub.1 and R.sub.2 are ethyl, R.sub.3 and R.sub.4 are both methyl,
and R.sub.5 and R.sub.6 are both --H; or R.sub.1 and R.sub.2 are
both n-propyl, R.sub.3 and R.sub.4 are both methyl, and R.sub.5 and
R.sub.6 are both --H.
[0073] In particular embodiments, the bis(thio-hydrazide amides)
are represented by Structural Formula IVb:
##STR00006##
[0074] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, wherein R.sub.1, R.sub.2, R.sub.3,
and R.sub.4 are as defined above for Structural Formula IVa.
[0075] In specific embodiments, the bis(thio-hydrazide amides) are
represented by Structural Formula V:
##STR00007##
[0076] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, wherein: R.sub.1 and R.sub.2 are
both phenyl, and R.sub.3 and R.sub.4 are both o-CH.sub.3-phenyl;
R.sub.1 and R.sub.2 are both o-CH.sub.3C(O)O-phenyl, and R.sub.3
and R.sub.4 are phenyl; R.sub.1 and R.sub.2 are both phenyl, and
R.sub.3 and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both
phenyl, and R.sub.3 and R.sub.4 are both ethyl; R.sub.1 and R.sub.2
are both phenyl, and R.sub.3 and R.sub.4 are both n-propyl; R.sub.1
and R.sub.2 are both p-cyanophenyl, and R.sub.3 and R.sub.4 are
both methyl; R.sub.1 and R.sub.2 are both p-nitro phenyl, and
R.sub.3 and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both
2,5-dimethoxyphenyl, and R.sub.3 and R.sub.4 are both methyl;
R.sub.1 and R.sub.2 are both phenyl, and R.sub.3 and R.sub.4 are
both n-butyl; R.sub.1 and R.sub.2 are both p-chlorophenyl, and
R.sub.3 and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both
3-nitrophenyl, and R.sub.3 and R.sub.4 are both methyl; R.sub.1 and
R.sub.2 are both 3-cyanophenyl, and R.sub.3 and R.sub.4 are both
methyl; R.sub.1 and R.sub.2 are both 3-fluorophenyl, and R.sub.3
and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both
2-furanyl, and R.sub.3 and R.sub.4 are both phenyl; R.sub.1 and
R.sub.2 are both 2-methoxyphenyl, and R.sub.3 and R.sub.4 are both
methyl; R.sub.1 and R.sub.2 are both 3-methoxyphenyl, and R.sub.3
and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both
2,3-dimethoxyphenyl, and R.sub.3 and R.sub.4 are both methyl;
R.sub.1 and R.sub.2 are both 2-methoxy-5-chlorophenyl, and R.sub.3
and R.sub.4 are both ethyl; R.sub.1 and R.sub.2 are both
2,5-difluorophenyl, and R.sub.3 and R.sub.4 are both methyl;
R.sub.1 and R.sub.2 are both 2,5-dichlorophenyl, and R.sub.3 and
R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both
2,5-dimethylphenyl, and R.sub.3 and R.sub.4 are both methyl;
R.sub.1 and R.sub.2 are both 2-methoxy-5-chlorophenyl, and R.sub.3
and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both
3,6-dimethoxyphenyl, and R.sub.3 and R.sub.4 are both methyl;
R.sub.1 and R.sub.2 are both phenyl, and R.sub.3 and R.sub.4 are
both 2-ethylphenyl; R.sub.1 and R.sub.2 are both
2-methyl-5-pyridyl, and R.sub.3 and R.sub.4 are both methyl; or
R.sub.1 is phenyl; R.sub.2 is 2,5-dimethoxyphenyl, and R.sub.3 and
R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both methyl, and
R.sub.3 and R.sub.4 are both p-CF.sub.3-phenyl; R.sub.1 and R.sub.2
are both methyl, and R.sub.3 and R.sub.4 are both
o-CH.sub.3-phenyl; R.sub.1 and R.sub.2 are both
--(CH.sub.2).sub.3COOH; and R.sub.3 and R.sub.4 are both phenyl;
R.sub.1 and R.sub.2 are both represented by the following
structural formula:
##STR00008##
and R.sub.3 and R.sub.4 are both phenyl; R.sub.1 and R.sub.2 are
both n-butyl, and R.sub.3 and R.sub.4 are both phenyl; R.sub.1 and
R.sub.2 are both n-pentyl, R.sub.3 and R.sub.4 are both phenyl;
R.sub.1 and R.sub.2 are both methyl, and R.sub.3 and R.sub.4 are
both 2-pyridyl; R.sub.1 and R.sub.2 are both cyclohexyl, and
R.sub.3 and R.sub.4 are both phenyl; R.sub.1 and R.sub.2 are both
methyl, and R.sub.3 and R.sub.4 are both 2-ethylphenyl; R.sub.1 and
R.sub.2 are both methyl, and R.sub.3 and R.sub.4 are both
2,6-dichlorophenyl; R.sub.1-R.sub.4 are all methyl; R.sub.1 and
R.sub.2 are both methyl, and R.sub.3 and R.sub.4 are both t-butyl;
R.sub.1 and R.sub.2 are both ethyl, and R.sub.3 and R.sub.4 are
both methyl; R.sub.1 and R.sub.2 are both t-butyl, and R.sub.3 and
R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both cyclopropyl,
and R.sub.3 and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are
both cyclopropyl, and R.sub.3 and R.sub.4 are both ethyl; R.sub.1
and R.sub.2 are both 1-methylcyclopropyl, and R.sub.3 and R.sub.4
are both methyl; R.sub.1 and R.sub.2 are both 2-methylcyclopropyl,
and R.sub.3 and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are
both 1-phenylcyclopropyl, and R.sub.3 and R.sub.4 are both methyl;
R.sub.1 and R.sub.2 are both 2-phenylcyclopropyl, and R.sub.3 and
R.sub.4 are both methyl; R.sub.1 and R.sub.2 are both cyclobutyl,
and R.sub.3 and R.sub.4 are both methyl; R.sub.1 and R.sub.2 are
both cyclopentyl, and R.sub.3 and R.sub.4 are both methyl; R.sub.1
is cyclopropyl, R.sub.2 is phenyl, and R.sub.3 and R.sub.4 are both
methyl.
[0077] Preferred examples of bis(thio-hydrazide amides) include
Compounds (1)-(18) and pharmaceutically acceptable salts and
solvates thereof:
##STR00009## ##STR00010## ##STR00011##
[0078] As used herein, the term "bis(thio-hydrazide amide)" and
references to the Structural Formulas of this invention also
include pharmaceutically acceptable salts and solvates of these
compounds and Structural Formulas. Examples of acceptable salts and
solvates are described in US Publication No.: 20060135595 and U.S.
patent application Ser. No. 11/432,307 filed 11 May 2006, titled
Synthesis Of Bis(Thio-Hydrazide Amide) Salts, the entire contents
of each of which are incorporated herein by reference.
[0079] These compounds can have one or more sufficiently acidic
proton that can react with a suitable organic or inorganic base to
form a base addition salt. Base addition salts include those
derived from inorganic bases, such as ammonium or alkali or
alkaline earth metal hydroxides, carbonates, bicarbonates, and the
like, and organic bases such as alkoxides, alkyl amides, alkyl and
aryl amines, and the like. Such bases useful in preparing the salts
of this invention thus include sodium hydroxide, potassium
hydroxide, ammonium hydroxide, potassium carbonate, and the
like.
[0080] For example, pharmaceutically acceptable salts of
bis(thio-hydrazide) amides employed herein (e.g., those represented
by Structural Formulas I-VI, Compounds 1-18) are those formed by
the reaction of the compound with one equivalent of a suitable base
to form a monovalent salt (i.e., the compound has single negative
charge that is balanced by a pharmaceutically acceptable counter
cation, e.g., a monovalent cation) or with two equivalents of a
suitable base to form a divalent salt (e.g., the compound has a
two-electron negative charge that is balanced by two
pharmaceutically acceptable counter cations, e.g., two
pharmaceutically acceptable monovalent cations or a single
pharmaceutically acceptable divalent cation). Divalent salts of the
bis(thio-hydrazide amides) are preferred. "Pharmaceutically
acceptable" means that the cation is suitable for administration to
a subject. Examples include Li.sup.+, Na.sup.+, Mg.sup.2+,
Ca.sup.2+ and NR.sub.4.sup.+, wherein each R is independently
hydrogen, an optionally substituted aliphatic group (e.g., a
hydroxyalkyl group, aminoalkyl group or ammoniumalkyl group) or
optionally substituted aryl group, or two R groups, taken together,
form an optionally substituted non-aromatic heterocyclic ring
optionally fused to an aromatic ring. Generally, the
pharmaceutically acceptable cation is Li.sup.+, Na.sup.+,
NH.sub.3(C.sub.2H.sub.5OH).sup.+ or
N(CH.sub.3).sub.3(C.sub.2H.sub.5OH).sup.+, and more typically, the
salt is a disodium or dipotassium salt, preferably the disodium
salt.
[0081] Bis(thio-hydrazide) amides employed herein having a
sufficiently basic group, such as an amine can react with an
organic or inorganic acid to form an acid addition salt. Acids
commonly employed to form acid addition salts from compounds with
basic groups are inorganic acids such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,
and the like, and organic acids such as p-toluenesulfonic acid,
methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid,
carbonic acid, succinic acid, citric acid, benzoic acid, acetic
acid, and the like. Examples of such salts include the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, isobutyrate, caproate,
heptanoate, propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,
xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,
citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, mandelate, and the like.
[0082] Salts of the disclosed bis(thiohydrazide amides) may have
tautomeric forms. By way of example, one tautomeric form for the
disalt is:
##STR00012##
[0083] Y is a covalent bond or a substituted or unsubstituted
straight chained hydrocarbyl group. R.sub.1-R.sub.4 are
independently --H, an aliphatic group, a substituted aliphatic
group, an aryl group or a substituted aryl group, or R.sub.1 and
R.sub.3 taken together with the carbon and nitrogen atoms to which
they are bonded, and/or R.sub.2 and R.sub.4 taken together with the
carbon and nitrogen atoms to which they are bonded, form a
non-aromatic heterocyclic ring optionally fused to an aromatic
ring. Z is --O or --S. M.sup.+ is a pharmaceutically acceptable
monovalent cation and M.sup.2+ is a pharmaceutically acceptable
divalent cation.
[0084] In one embodiment, the variables for Structural Formula (VI)
are defined below:
[0085] M.sup.+ is a pharmaceutically acceptable monovalent cation.
M.sup.2+ is a pharmaceutically acceptable divalent cation.
"Pharmaceutically acceptable" means that the cation is suitable for
administration to a subject. Examples of M.sup.+ or M.sup.2+
include Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+,
Zn.sup.2+, and NR.sub.4.sup.+, wherein each R is independently
hydrogen, a substituted or unsubstituted aliphatic group (e.g., a
hydroxyalkyl group, aminoalkyl group or ammoniumalkyl group) or
substituted or unsubstituted aryl group, or two R groups, taken
together, form a substituted or unsubstituted non-aromatic
heterocyclic ring optionally fused to an aromatic ring. Preferably,
the pharmaceutically acceptable cation is Li.sup.+, Na.sup.+,
K.sup.+, NH.sub.3(C.sub.2H.sub.5OH).sup.+,
N(CH.sub.3).sub.3(C.sub.2H.sub.5OH).sup.+, arginine or lysine. More
preferably, the pharmaceutically acceptable cation is Na.sup.+ or
K.sup.+. Na.sup.+ is even more preferred.
[0086] Exemplary tautomeric forms of the disalt compounds
represented by Structural Formula (VI) wherein Y is --CH.sub.2--
are shown below:
##STR00013##
Representative tautomeric structures of the disalt of Compound (1)
are shown below:
##STR00014##
[0087] Preferred examples of bis(thio-hydrazide amide) disalts of
the present invention are the following:
##STR00015##
2 M.sup.+ and M.sup.2+ are as described above for Structural
Formula (VI). Preferably, the pharmaceutically acceptable cation is
2 M.sup.+, wherein M.sup.+ is Li.sup.+, Na.sup.+, K.sup.+,
NH.sub.3(C.sub.2H.sub.5OH).sup.+ or
N(CH.sub.3).sub.3(C.sub.2H.sub.5OH).sup.+. More preferably, M.sup.+
is Na.sup.+ or K. Even more preferably, M.sup.+ is Na.sup.+.
[0088] It is to be understood when one tautomeric form of a
disclosed compound is depicted structurally, other tautomeric forms
are also encompassed.
[0089] Certain compounds of the invention may be obtained as
different stereoisomers (e.g., diastereomers and enantiomers). The
invention includes all isomeric forms and racemic mixtures of the
disclosed compounds and methods of treating a subject with both
pure isomers and mixtures thereof, including racemic mixtures.
Stereoisomers can be separated and isolated using any suitable
method, such as chromatography.
[0090] As used herein, the term "clathrate" means a compound of the
present invention or a salt thereof in the form of a crystal
lattice that contains spaces (e.g., channels) that have a guest
molecule (e.g., a solvent or water) trapped within.
[0091] As used herein and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide a compound of this invention. Prodrugs may
become active upon such reaction under biological conditions, or
they may have activity in their unreacted forms. Examples of
prodrugs contemplated in this invention include, but are not
limited to, analogs or derivatives of compounds of formula (I)
through (XII) and Table 1 that comprise biohydrolyzable moieties
such as biohydrolyzable amides, biohydrolyzable esters,
biohydrolyzable carbamates, biohydrolyzable carbonates,
biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
Other examples of prodrugs include derivatives of compounds of
formula (I) through (XII) and Table 1, that comprise --NO,
--NO.sub.2, --ONO, or --ONO.sub.2 moieties. Prodrugs can typically
be prepared using well-known methods, such as those described by 1
BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178,
949-982 (Manfred E. Wolff ed., 5.sup.th ed).
[0092] As used herein and unless otherwise indicated, the terms
"biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable
carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide"
and "biohydrolyzable phosphate analogue" mean an amide, ester,
carbamate, carbonate, ureide, or phosphate analogue, respectively,
that either: 1) does not destroy the biological activity of the
compound and confers upon that compound advantageous properties in
vivo, such as improved water solubility, improved circulating
half-life in the blood (e.g., because of reduced metabolism of the
prodrug), improved uptake, improved duration of action, or improved
onset of action; or 2) is itself biologically inactive but is
converted in vivo to a biologically active compound. Examples of
biohydrolyzable amides include, but are not limited to, lower alkyl
amides, .alpha.-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters
include, but are not limited to, lower alkyl esters, alkoxyacyloxy
esters, alkyl acylamino alkyl esters, and choline esters. Examples
of biohydrolyzable carbamates include, but are not limited to,
lower alkylamines, substituted ethylenediamines, aminoacids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and
polyether amines.
[0093] An "alkyl group" is saturated straight or branched chain
linear or cyclic hydrocarbon group. Typically, a straight chained
or branched alkyl group has from 1 to about 20 carbon atoms,
preferably from 1 to about 10, and a cyclic alkyl group has from 3
to about 10 carbon atoms, preferably from 3 to about 8. An alkyl
group is preferably a straight chained or branched alkyl group,
e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,
tert-butyl, pentyl, hexyl, pentyl or octyl, or a cycloalkyl group
with 3 to about 8 carbon atoms. A C1-C8 straight chained or
branched alkyl group or a C3-C8 cyclic alkyl group is also referred
to as a "lower alkyl" group. Suitable substitutents for an alkyl
group are those which do not substantially interfere with the
anti-cancer activity of the disclosed compounds. Suitable
substituents are as described below for aliphatic groups. Preferred
substituents on alkyl groups include, --OH, --NH.sub.2, --NO.sub.2,
--CN, --COOH, halogen, aryl, C1-C8 alkoxy, C1-C8 haloalkoxy and
--CO(C1-C8 alkyl). More preferred substituents on alkyl groups
include --OH, halogen, phenyl, benzyl, pyridyl, and C1-C8 alkoxy.
More preferred substituents on alkyl groups include --OH, halogen,
and C1-C4 alkoxy.
[0094] A "straight chained hydrocarbyl group" is an alkylene group,
i.e., --(CH.sub.2).sub.y--, with one or more (preferably one)
internal methylene groups optionally replaced with a linkage group.
y is a positive integer (e.g., between 1 and 10), preferably
between 1 and 6 and more preferably 1 or 2. A "linkage group"
refers to a functional group which replaces a methylene in a
straight chained hydrocarbyl. Examples of suitable linkage groups
include a ketone (--C(O)--), alkene, alkyne, phenylene, ether
(--O--), thioether (--S--), or amine (--N(R.sup.a)--), wherein
R.sup.a is defined below. A preferred linkage group is
--C(R.sub.5R.sub.6)--, wherein R.sub.5 and R.sub.6 are defined
above. Suitable substitutents for an alkylene group and a
hydrocarbyl group are those which do not substantially interfere
with the anti-cancer activity of the disclosed compounds. R.sub.5
and R.sub.6 are preferred substituents for an alkylene or
hydrocarbyl group represented by Y.
[0095] An aliphatic group is a straight chained, branched or cyclic
non-aromatic hydrocarbon which is completely saturated or which
contains one or more units of unsaturation. Typically, a straight
chained or branched aliphatic group has from 1 to about 20 carbon
atoms, preferably from 1 to about 10, and a cyclic aliphatic group
has from 3 to about 10 carbon atoms, preferably from 3 to about 8.
An aliphatic group is preferably a straight chained or branched
alkyl group, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, tert-butyl, pentyl, hexyl, pentyl or octyl, or a
cycloalkyl group with 3 to about 8 carbon atoms. A C1-C8 straight
chained or branched alkyl group or a C3-C8 cyclic alkyl group is
also referred to as a "lower alkyl" group.
[0096] The term "aromatic group" may be used interchangeably with
"aryl," "aryl ring," "aromatic ring," "aryl group" and "aromatic
group." Aromatic groups include carbocyclic aromatic groups such as
phenyl, naphthyl, and anthracyl, and heteroaryl groups such as
imidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl,
pyrazolyl, pyrroyl, pyrazinyl, thiazole, oxazolyl, and tetrazole.
The term "heteroaryl group" may be used interchangeably with
"heteroaryl," "heteroaryl ring," "heteroaromatic ring" and
"heteroaromatic group." Heteroaryl groups are aromatic groups that
comprise one or more heteroatom, such as sulfur, oxygen and
nitrogen, in the ring structure. Preferably, heteroaryl groups
comprise from one to four heteroatoms.
[0097] Aromatic groups also include fused polycyclic aromatic ring
systems in which a carbocyclic aromatic ring or heteroaryl ring is
fused to one or more other heteroaryl rings. Examples include
benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazole,
benzooxazole, benzimidazole, quinolinyl, isoquinolinyl and
isoindolyl.
[0098] Non-aromatic heterocyclic rings are non-aromatic rings which
include one or more heteroatoms such as nitrogen, oxygen or sulfur
in the ring. The ring can be five, six, seven or eight-membered.
Preferably, heterocyclic groups comprise from one to about four
heteroatoms. Examples include tetrahydrofuranyl,
tetrahyrothiophenyl, morpholino, thiomorpholino, pyrrolidinyl,
piperazinyl, piperidinyl, and thiazolidinyl.
[0099] Suitable substituents on an aliphatic group (including an
alkylene group), non-aromatic heterocyclic group, benzylic or aryl
group (carbocyclic and heteroaryl) are those which do not
substantially interfere with the anti-cancer activity of the
disclosed compounds. A substituent substantially interferes with
anti-cancer activity when the anti-cancer activity is reduced by
more than about 50% in a compound with the substituent compared
with a compound without the substituent. Examples of suitable
substituents include --R.sup.a, --OH, --Br, --Cl, --I, --F,
--OR.sup.a, --O--COR.sup.a, --COR.sup.a, --CN, --NO.sub.2, --COOH,
--SO.sub.3H, --NH.sub.2, --NHR.sup.a, --N(R.sup.aR.sup.b),
--COOR.sup.a, --CHO, --CONH.sub.2, --CONHR.sup.a,
--CON(R.sup.aR.sup.b), --NHCOR.sup.a, --NR.sup.cCOR.sup.a,
--NHCONH.sub.2, --NHCONR.sup.aH, --NHCON(R.sup.aR.sup.b),
--NR.sup.cCONH.sub.2, --NR.sup.cCONR.sup.aH,
--NR.sup.cCON(R.sup.aR.sup.b), --C(.dbd.NH)--NH.sub.2,
--C(.dbd.NH)--NHR.sup.a, --C(.dbd.NH)--N(R.sup.aR.sup.b),
--C(.dbd.NR.sup.c)--NH.sub.2, --C(.dbd.NR.sup.c)--NHR.sup.a,
--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NH--C(.dbd.NH)--NH.sub.2,
--NH--C(.dbd.NH)--NHR.sup.a, --NH--C(.dbd.NH)--N(R.sup.aR.sup.b),
--NH--C(.dbd.NR.sup.c)--NH.sub.2,
--NH--C(.dbd.NR.sup.c)--NHR.sup.a,
--NH--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b),
--NR.sup.dH--C(.dbd.NH)--NH.sub.2,
--NR.sup.d--C(.dbd.NH)--NHR.sup.a,
--NR.sup.d--C(.dbd.NH)--N(R.sup.aR.sup.b),
--NR.sup.d--C(.dbd.NR.sup.c)--NH.sub.2,
--NR.sup.d--C(.dbd.NR.sup.c)--NHR.sup.a,
--NR.sup.d--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NHNH.sub.2,
--NHNHR.sup.a, --NHR.sup.aR.sup.b, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.a, --SO.sub.2NR.sup.aR.sup.b, --CH.dbd.CHR.sup.a,
--CH.dbd.CR.sup.aR.sup.b, --CR.sup.c.dbd.CR.sup.aR.sup.b,
--CR.sup.c.dbd.CHR.sup.a, --CR.sup.c.dbd.CR.sup.aR.sup.b,
--CCR.sup.a, --SH, --SR.sup.a, --S(O)R.sup.a,
--S(O).sub.2R.sup.a.
[0100] R.sup.a-R.sup.d are each independently an alkyl group,
aromatic group, non-aromatic heterocyclic group or
--N(R.sup.aR.sup.b), taken together, form a non-aromatic
heterocyclic group. The alkyl, aromatic and non-aromatic
heterocyclic group represented by R.sup.a-R.sup.d and the
non-aromatic heterocyclic group represented by --N(R.sup.aR.sup.b)
are each optionally and independently substituted with one or more
groups represented by R.sup.#. Preferably R.sup.a-R.sup.d are
unsubstituted.
[0101] R.sup.# is R.sup.+, --OR.sup.+, --O(haloalkyl), --SR.sup.+,
--NO.sub.2, --CN, --NCS, --N(R.sup.+).sub.2, --NHCO.sub.2R.sup.+,
--NHC(O)R.sup.+, --NHNHC(O)R.sup.+, --NHC(O)N(R.sup.+).sub.2,
--NHNHC(O)N(R.sup.+).sub.2, --NHNHCO.sub.2R.sup.+,
--C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --CO.sub.2R.sup.+,
--C(O)R.sup.+, --C(O)N(R.sup.+).sub.2, --OC(O)R.sup.+,
--OC(O)N(R.sup.+).sub.2, --S(O).sub.2R.sup.+,
--SO.sub.2N(R.sup.+).sub.2, --S(O)R.sup.+,
--NHSO.sub.2N(R.sup.+).sub.2, --NHSO.sub.2R.sup.+,
--C(.dbd.S)N(R.sup.+).sub.2, or --C(.dbd.NH)--N(R.sup.+).sub.2.
[0102] R.sup.+ is --H, a C1-C4 alkyl group, a monocyclic heteroaryl
group, a non-aromatic heterocyclic group or a phenyl group
optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy,
halo, --CN, --NO.sub.2, amine, alkylamine or dialkylamine.
Preferably R.sup.+ is unsubstituted. Optionally, the group
--N(R.sup.+).sub.2 is a non-aromatic heterocyclic group, provided
that non-aromatic heterocyclic groups represented by R and
--N(R.sup.+).sub.2 that comprise a secondary ring amine are
optionally acylated or alkylated.
[0103] Preferred substituents for a phenyl group, including phenyl
groups represented by R.sub.1-R.sub.4, include C1-C4 alkyl, C1-C4
alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, benzyl, pyridyl,
--OH, --NH.sub.2, --F, --Cl, --Br, --I, --NO.sub.2 or --CN. More
preferred for a phenyl group, including phenyl groups represented
by R.sub.1-R.sub.4, include R.sub.1 and R.sub.2 are optionally
substituted with --OH, --CN, halogen, C1-4 alkyl or C1-C4
alkoxy
[0104] Preferred substituents for a cycloalkyl group, including
cycloalkyl groups represented by R.sub.1 and R.sub.2, are alkyl
groups, such as a methyl or ethyl group.
[0105] Other anti-proliferative or anticancer therapies may be
combined with the compounds of this invention to treat
proliferative diseases and cancer. Other therapies or anticancer
agents that may be used in combination with the inventive
anticancer agents of the present invention include surgery,
radiotherapy (including, but not limited to, gamma-radiation,
neutron beam radiotherapy, electron beam radiotherapy, proton
therapy, brachytherapy, and systemic radioactive isotopes),
endocrine therapy, biologic response modifiers (including, but not
limited to, interferons, interleukins, and tumor necrosis factor
(TNF)), hyperthermia and cryotherapy, agents to attenuate any
adverse effects (e.g., antiemetics), and other approved
chemotherapeutic drugs.
[0106] The prophylactic or therapeutic agents of the combination
therapies of the invention can be administered sequentially or
concurrently.
[0107] As used herein, the terms "hyperthermia", "hyperthermia
therapy," "thermal therapy," and "thermotherapy" are used
interchangeably to mean a treatment where body tissue is exposed to
high temperatures (up to 113.degree. F.). The term as used herein
includes all forms of hyperthermia, including local, regional, and
whole-body. Various forms of energy can be used to deliver heat to
the desired area, such as microwave, radiofrequency, lasers, and
ultrasound. The treatment temperatures vary depending on the
location of the tumor and the approach used.
[0108] In local hyperthermia, heat is applied to a small area (e.g.
a tumor). The approaches to local hyperthermia vary with tumor
location. External approaches are used to treat tumors in or just
below the skin. In this method, applicators are place near or
around the tumor and deliver energy directly to the tumor.
Intraluminal or endocavitary approaches use probes to deliver
energy to tumors within or near body cavities. Interstitial
approaches are used to treat tumors deep within the body (e.g.
brain tumors), by inserting probes or needles into the tumor under
anesthesia.
[0109] In regional hyperthermia, heat is applied to large areas of
tissue (e.g. body cavity, organ, or limb). Deep tissue approaches
are used to treat cancers within the body (e.g. cervical or bladder
cancer) by using external applicators. Regional perfusion
approaches are used to treat cancers in the limbs or organs (e.g.
melanoma, liver, or lung cancer). In this approach some of the
blood is removed and heated and then pumped back into the limb or
organ. Anticancer drugs may be given during this process.
Continuous hyperthermic peritoneal perfusion (CHPP) is used to
treat cancers in the peritoneal cavity (e.g. peritoneal
mesothelioma or stomach cancer). In this approach, heated
anticancer drugs are pumped through the peritoneal cavity.
[0110] Whole-body hyperthermia is used to treat metastatic cancer.
In this approach, the whole body is heated to 107-108.degree. F. by
using various techniques such as thermal chambers or hot water
blankets.
[0111] Hyperthermic conditions are known to induce the synthesis of
Hsp70.
[0112] As used herein, "Hsp70" includes each member of the family
of heat shock proteins having a mass of about 70-kiloDaltons,
including forms such as constitutive, cognate, cell-specific,
glucose-regulated, inducible, etc. Examples of specific Hsp70
proteins include hsp70, hsp70hom; hsc70; Grp78/BiP; mt-hsp70/Grp75,
and the like). Typically, the disclosed methods increase expression
of inducible Hsp70. Functionally, the 70-kDa HSP(HSP70) family is a
group of chaperones that assist in the folding, transport, and
assembly of proteins in the cytoplasm, mitochondria, and
endoplasmic reticulum. Membrane-bound Hsp70 In humans, the Hsp70
family encompasses at least 11 genes encoding a group of highly
related proteins. See, for example, Tavaria, et al., Cell Stress
Chaperones, 1996; 1(1):23-28; Todryk, et al., Immunology. 2003,
110(1): 1-9; and Georgopoulos and Welch, Annu Rev Cell Biol. 1993;
9:601-634; the entire teachings of these documents are incorporated
herein by reference.
[0113] Immunotherapy (also called biological response modifier
therapy, biologic therapy, biotherapy, immune therapy, or
biological therapy) is treatment that uses parts of the immune
system to fight disease. Immunotherapy can help the immune system
recognize cancer cells, or enhance a response against cancer cells.
Immunotherapies include active and passive immunotherapies. Active
immunotherapies stimulate the body's own immune system while
passive immunotherapies generally use immune system components
created outside of the body.
[0114] Examples of active immunotherapies include, but are not
limited to vaccines including cancer vaccines, tumor cell vaccines
(autologous or allogeneic), viral vaccines, dendritic cell
vaccines, antigen vaccines, anti-idiotype vaccines, DNA vaccines,
or Tumor-Infiltrating Lymphocyte (TIL) Vaccine with Interleukin-2
(IL-2) or Lymphokine-Activated Killer (LAK) Cell Therapy.
[0115] Examples of passive immunotherapies include but are not
limited to monoclonal antibodies and targeted therapies containing
toxins. Monoclonal antibodies include naked antibodies and
conjugated antibodies (also called tagged, labeled, or loaded
antibodies). Naked monoclonal antibodies do not have a drug or
radioactive material attached whereas conjugated monoclonal
antibodies are joined to, for example, a chemotherapy drug
(chemolabeled), a radioactive particle (radiolabeled), or a toxin
(immunotoxin).
[0116] In certain embodiments of the present invention passive
immunotherapies, such as, naked monoclonal antibody drugs can be
used in combination with the bis(thio hydrazide amides) described
herein to treat cancer in the methods of the present invention.
Examples of these naked monoclonal antibody drugs include, but are
not limited to Rituximab (Rituxan), an antibody against the CD20
antigen used to treat, for example, B cell non-Hodgkin lymphoma;
Trastuzumab (Herceptin), an antibody against the HER2 protein used
to treat, for example, advanced breast cancer; Alemtuzumab
(Campath), an antibody against the CD52 antigen used to treat, for
example, B cell chronic lymphocytic leukemia (B-CLL); Cetuximab
(Erbitux), an antibody against the EGFR protein used, for example,
in combination with irinotecan to treat, for example, advanced
colorectal cancer and head and neck cancers; and Bevacizumab
(Avastin) which is an antiangiogenesis therapy that works against
the VEGF protein and is used, for example, in combination with
chemotherapy to treat, for example, metastatic colorectal
cancer.
[0117] Further examples of therapeutic antibodies that can be used
include, but are not limited to, HERCEPTIN.RTM. (Trastuzumab)
(Genentech, Calif.) which is a humanized anti-HER2 monoclonal
antibody for the treatment of patients with metastatic breast
cancer; REOPRO.RTM. (abciximab) (Centocor) which is an
anti-glycoprotein IIb/IIIa receptor on the platelets for the
prevention of clot formation; ZENAPAX.RTM. (daclizumab) (Roche
Pharmaceuticals, Switzerland) which is an immunosuppressive,
humanized anti-CD25 monoclonal antibody for the prevention of acute
renal allograft rejection; PANOREX.TM. which is a murine anti-17-IA
cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2
which is a murine anti-idiotype (GD3 epitope) IgG antibody (ImClone
System); IMC-C225 which is a chimeric anti-EGFR IgG antibody
(ImClone System); VITAXIN.TM. which is a humanized
anti-.alpha.V.beta.3 integrin antibody (Applied Molecular
Evolution/MedImmune); Campath 1H/LDP-03 which is a humanized anti
CD52 IgG1 antibody (Leukosite); Smart M195 which is a humanized
anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAN.TM.
which is a chimeric anti-CD20 IgG1 antibody (IDEC Pharm/Genentech,
Roche/Zettyaku); LYMPHOCIDE.TM. which is a humanized anti-CD22 IgG
antibody (Immunomedics); LYMPHOCIDE.TM. Y-90 (Immunomedics);
Lymphoscan (Tc-99m-labeled; radioimaging; Immunomedics); Nuvion
(against CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3
antibody (ICOS Pharm); IDEC-114 is a primatied anti-CD80 antibody
(IDEC Pharm/Mitsubishi); ZEVALIN.TM. is a radiolabelled murine
anti-CD20 antibody (IDEC/Schering AG); IDEC-131 is a humanized
anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primatized anti-CD4
antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody
(IDEC/Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG
(Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5
(C5) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF-.alpha.
antibody (CAT/BASF); CDP870 is a humanized anti-TNF-.alpha. Fab
fragment (Celltech); IDEC-151 is a primatized anti-CD4 IgG1
antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human
anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-sreptdavidin
(+biotin-yttrium 90; NeoRx); CDP571 is a humanized anti-TNF-.alpha.
IgG4 antibody (Celltech); LDP-02 is a humanized
anti-.alpha.4.beta.7 antibody (LeukoSite/Genentech); OrthoClone
OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech);
ANTOVA.TM. is a humanized anti-CD40L IgG antibody (Biogen);
ANTEGREN.TM. is a humanized anti-VLA-4 IgG antibody (Elan); and
CAT-152 is a human anti-TGF-.beta..sub.2 antibody (Cambridge Ab
Tech).
[0118] In certain embodiments of the present invention passive
immunotherapies, such as, conjugated monoclonal antibodies can be
used in combination with the bis(thio hydrazide amides) described
herein to treat cancer in the methods of the present invention.
Examples of these conjugated monoclonal antibodies include, but are
not limited to Radiolabeled antibody Ibritumomab tiuxetan (Zevalin)
which delivers radioactivity directly to cancerous B lymphocytes
and is used to treat, for example, B cell non-Hodgkin lymphoma;
radiolabeled antibody Tositumomab (Bexxar) which is used to treat,
for example, certain types of non-Hodgkin lymphoma; and immunotoxin
Gemtuzumab ozogamicin (Mylotarg) which contains calicheamicin and
is used to treat, for example, acute myelogenous leukemia (AML).
BL22 is a conjugated monoclonal antibody for treating, for example,
hairy cell leukemia, immunotoxins for treating, for example,
leukemias, lymphomas, and brain tumors, and radiolabeled antibodies
such as OncoScint for example, for colorectal and ovarian cancers
and ProstaScint for example, for prostate cancers.
[0119] In certain embodiments of the present invention targeted
therapies containing toxins can be used in combination with the
bis(thio hydrazide amides) described herein to treat cancer in the
methods of the present invention. Targeted therapies containing
toxins are toxins linked to growth factors and do not contain
antibodies, for example, denileukin diftitox (Ontak) which can be
used to treat, for example, skin lymphoma (cutaneous T cell
lymphoma) in combination with the bis(thiohydrazide amides)
described herein.
[0120] The present invention also includes the use of adjuvant
immunotherapies in combination with the bis(thio hydrazide amides)
described herein include, such adjuvant immunotherapies include,
but are not limited to, cytokines, such as granulocyte-macrophage
colony-stimulating factor (GM-CSF), granulocyte-colony stimulating
factor (G-CSF), macrophage inflammatory protein (MIP)-1-alpha,
interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15,
IL-18, IL-21, and IL-27), tumor necrosis factors (including
TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and
IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guerin
(BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's
adjuvant (IFA); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP),
and combinations thereof, such as, for example, combinations of,
interleukins, for example, IL-2 with other cytokines, such as
IFN-alpha.
[0121] In certain embodiments the immunotherapies described herein
can be used in combination with the bis(thio hydrazide amides)
described herein for use in the methods of the present invention.
In one such embodiment, the method of the present invention is a
method of treating melanoma with a combination of an effective
amount of a bisthio(hydrazide amide), hyperthermia treatment, and
optionally an effective amount of an immunotherapy.
[0122] In certain embodiments the immunotherapies described herein
can be used in combination with the bis(thio hydrazide amides)
described herein for use in the methods of the present invention.
In one such embodiment, the method of the present invention is a
method of treating melanoma with a combination of an effective
amount of a bisthio(hydrazide amide), radiotherapy, and optionally
an effective amount of an immunotherapy.
[0123] Examples of immunotherapies which are suitable in this
method and other methods of the invention include:
[0124] IFN-alpha and IL-2 for treatment of, for example, metastatic
melanoma; BCG in combination with, for example, melanoma vaccines
and optionally other immunotherapies; tumor-infiltrating
lymphocytes; human monoclonal antibodies to ganglioside antigens,
to treat, for example, cutaneous recurrent melanoma tumors;
autologous and allogeneic tumor cell vaccines, antigen vaccines
(including polyvalent antigen vaccines), dendritic cell vaccines;
viral vaccines; combined IL-12/TNF-alpha immunotherapy to treat,
foe example, B16F10 melanoma, Lewis lung (LL/2) carcinoma and L1
sarcoma; and IFN-alpha to treat, for example, malignant melanoma,
chronic myelogenous leukemia (CML), hairy cell leukemia, and
Kaposi's sarcoma.
[0125] In certain embodiments the immunotherapies described herein
can be used in combination with the bis(thio hydrazide amides)
described herein for use in the methods of the present invention.
In one such embodiment, the method of the present invention is a
method of treating renal cancer with a combination of an effective
amount of a bisthio(hydrazide amide), hyperthermia treatment, and
optionally an effective amount of an immunotherapy.
[0126] In certain embodiments the immunotherapies described herein
can be used in combination with the bis(thio hydrazide amides)
described herein for use in the methods of the present invention.
In one such embodiment, the method of the present invention is a
method of treating renal cancer with a combination of an effective
amount of a bisthio(hydrazide amide), radiotherapy, and optionally
an effective amount of an immunotherapy
[0127] Examples of immunotherapies which are suitable in this
method and other methods of the invention include:
[0128] IFN-alpha and IL-2 alone or in combination; combination of
IL-2, interferon and chemotherapy; a tumor cell vaccine plus the
adjuvant BCG; DNA vaccines and tumor-infiltrating lymphocytes; and
chimeric bispecific G250/anti-CD3 monoclonal antibodies.
[0129] In certain embodiments the present invention is directed to
administering an effective amount of a bis(thiohydrazide amide and
an effective amount of rapamycin, geldenamyci, 17-allylamino,
17-demethoxygeldanamycin, histone deacetylase inhibitors,
topoisomerase I inhibitors, thioredoxin 1 inhibitors, mictotubule
disruptors, Epothilone, EP0906, an allogenic bone marrow stem cell
transplantation, allogenic hematopoietic stem cell transplantation,
PTK 787, SU 11248 bey 43-9006, medroxyprogestterone, ABX-EGF,
imatinib mesylate, ZD1839, SU5416, bortezomib (PS-341), BAY
59-8862, HSPPC-96, thalidomide ABT-510, CCI-779 or RAD-001, or
combinations of bevacizumab and thalidomide, or combinations of
thalidomide and IFN-.alpha., or combinations of FUNIL and
thalidomide, or combinations of CAPE and IFN-.alpha., or
combinations of gemcitabine (GEM) and capecitabine (CAPE), or
combinations of thalidomide and IL-2, and thalidomide, or
combinations of HSPPC-96 and IL-2 or a combination of bevacizumab,
IL-2, interferon and optionally an additional anti-cancer
agent.
[0130] In a particular embodiment, the method of the present
invention comprises administering to a subject with an
immunosensitive cancer an effective amount of the bis(thiohydrazide
amide) described herein, hyperthermia treatment, an effective
amount of the immunotherapy described herein and one or more
additional anti-cancer therapies selected from: anti-cancer
agents/drugs, biological therapy, radiation therapy,
anti-angiogenesis therapy, gene therapy or hormonal therapy.
[0131] In a particular embodiment, the method of the present
invention comprises administering to a subject with an
immunosensitive cancer an effective amount of the bis(thiohydrazide
amide) described herein, radiation therapy, an effective amount of
the immunotherapy described herein and one or more additional
anti-cancer therapies selected from: anti-cancer agents/drugs,
biological therapy, hyperthermia treatment, anti-angiogenesis
therapy, gene therapy or hormonal therapy.
[0132] Examples of anti-cancer agents/drugs are described
below.
[0133] In one embodiment the anti-cancer agents/drug is, for
example, Adriamycin, Dactinomycin, Bleomycin, Vinblastine,
Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;
acronine; adozelesin; aldesleukin; altretamine; ambomycin;
ametantrone acetate; aminoglutethimide; amsacrine; anastrozole;
anthramycin; asparaginase; asperlin; azacitidine; azetepa;
azotomycin; batimastat; benzodepa; bicalutamide; bisantrene
hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;
brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;
dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin
hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan
hydrochloride; lanreotide acetate; letrozole; leuprolide acetate;
liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium; porfiromycin; prednimustine; procarbazine hydrochloride;
puromycin; puromycin hydrochloride; pyrazofurin; riboprine;
rogletimide; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin
hydrochloride.
[0134] Other anti-cancer agents/drugs include, but are not limited
to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; iobenguane;
iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leuprolide+estrogen+progesterone; leuprorelin;
levamisole; liarozole; linear polyamine analogue; lipophilic
disaccharide peptide; lipophilic platinum compounds; lissoclinamide
7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain
antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate;
sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
Preferred additional anti-cancer drugs are 5-fluorouracil and
leucovorin.
[0135] Agents that can be used in the methods of the invention in
combination with the bis(thiohydrazide amides) in the methods
disclosed herein, include but are not limited to, alkylating
agents, antimetabolites, natural products, or hormones. Examples of
alkylating agents useful in the methods of the invention include
but are not limited to, nitrogen mustards (e.g., mechloroethamine,
cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and
methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl
sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,
lomustine, semustine, streptozocin, etc.), or triazenes
(decarbazine, etc.). Examples of antimetabolites useful in the
methods of the invention include but are not limited to folic acid
analog (e.g., methotrexate), or pyrimidine analogs (e.g.,
fluorouracil, floxouridine, Cytarabine), purine analogs (e.g.,
mercaptopurine, thioguanine, pentostatin). Examples of natural
products useful in the methods of the invention include but are not
limited to vinca alkaloids (e.g., vinblastin, vincristine),
epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics
(e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin,
plicamycin, mitomycin) or enzymes (e.g., L-asparaginase). Examples
of hormones and antagonists useful for the treatment or prevention
of cancer in the methods of the invention include but are not
limited to adrenocorticosteroids (e.g., prednisone), progestins
(e.g., hydroxyprogesterone caproate, megestrol acetate,
medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,
ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens
(e.g., testosterone propionate, fluoxymesterone), antiandrogen
(e.g., flutamide), gonadotropin releasing hormone analog (e.g.,
leuprolide). Other agents that can be used in the methods of the
invention for the treatment or prevention of cancer include
platinum coordination complexes (e.g., cisplatin, carboblatin),
anthracenedione (e.g., mitoxantrone), substituted urea (e.g.,
hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),
adrenocortical suppressant (e.g., mitotane, aminoglutethimide).
[0136] Preferably, the anti-cancer agent/drug is an agent that
stabilizes microtubules. As used herein, a "microtubulin
stabilizer" means an anti-cancer agent/drug which acts by arresting
cells in the G2-M phases due to stabilization of microtubules.
Examples of microtubulin stabilizers include ACLITAXEL.RTM. and
Taxol.RTM. analogues. Additional examples of microtubulin
stabilizers included without limitation the following marketed
drugs and drugs in development: Discodermolide (also known as
NVP-XX-A-296); Epothilones (such as Epothilone A, Epothilone B,
Epothilone C (also known as desoxyepothilone A or dEpoA);
Epothilone D (also referred to as KOS-862, dEpoB, and
desoxyepothilone B); Epothilone E; Epothilone F; Epothilone B
N-oxide; Epothilone A N-oxide; 16-aza-epothilone B;
21-aminoepothilone B (also known as BMS-310705);
21-hydroxyepothilone D (also known as Desoxyepothilone F and
dEpoF), 26-fluoroepothilone); FR-182877 (Fujisawa, also known as
WS-9885B), BSF-223651 (BASF, also known as ILX-651 and LU-223651);
AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl); AC-7700
(Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and
RPR-258062A); Fijianolide B; Laulimalide; Caribaeoside;
Caribaeolin; Taccalonolide; Eleutherobin; Sarcodictyin;
Laulimalide; Dictyostatin-1; Jatrophane esters; and analogs and
derivatives thereof.
[0137] As used herein, a "microtubulin inhibitor" means an
anti-cancer agent which acts by inhibiting tubulin polymerization
or microtubule assembly. Examples of microtubulin inhibitors
include without limitation the following marketed drugs and drugs
in development: Erbulozole (also known as R-55104); Dolastatin 10
(also known as DLS-10 and NSC-376128); Mivobulin isethionate (also
known as CI-980); Vincristine; NSC-639829; ABT-751 (Abbot, also
known as E-7010); Altorhyrtins (such as Altorhyrtin A and
Altorhyrtin C); Spongistatins (such as Spongistatin 1, Spongistatin
2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6,
Spongistatin 7, Spongistatin 8, and Spongistatin 9); Cemadotin
hydrochloride (also known as LU-103793 and NSC-D-669356);
Auristatin PE (also known as NSC-654663); Soblidotin (also known as
TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577); LS-4578
(Pharmacia, also known as LS-477-P); LS-4477 (Pharmacia), LS-4559
(Pharmacia); RPR-112378 (Aventis); Vincristine sulfate; DZ-3358
(Daiichi); GS-164 (Takeda); GS-198 (Takeda); KAR-2 (Hungarian
Academy of Sciences); SAH-49960 (Lilly/Novartis); SDZ-268970
(Lilly/Novartis); AM-97 (Armad/Kyowa Hakko); AM-132 (Armad); AM-138
(Armad/Kyowa Hakko); IDN-5005 (Indena); Cryptophycin 52 (also known
as LY-355703); Vitilevuamide; Tubulysin A; Canadensol; Centaureidin
(also known as NSC-106969); T-138067 (Tularik, also known as T-67,
TL-138067 and TI-138067); COBRA-1 (Parker Hughes Institute, also
known as DDE-261 and WHI-261); H10 (Kansas State University); H16
(Kansas State University); Oncocidin A1 (also known as BTO-956 and
DIME); DDE-313 (Parker Hughes Institute); SPA-2 (Parker Hughes
Institute); SPA-1 (Parker Hughes Institute, also known as
SPIKET-P); 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also
known as MF-569); Narcosine (also known as NSC-5366); Nascapine,
D-24851 (Asta Medica), A-105972 (Abbott); Hemiasterlin; 3-BAABU
(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191);
TMPN (Arizona State University); Vanadocene acetylacetonate;
T-138026 (Tularik); Monsatrol; Inanocine (also known as
NSC-698666); 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine);
A-204197 (Abbott); T-607 (Tularik, also known as T-900607);
RPR-115781 (Aventis); Eleutherobins (such as Desmethyleleutherobin,
Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin);
Halichondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica);
Diazonamide A; A-293620 (Abbott); NPI-2350 (Nereus); TUB-245
(Aventis); A-259754 (Abbott); Diozostatin; (-)-Phenylahistin (also
known as NSCL-96F037); D-68838 (Asta Medica); D-68836 (Asta
Medica); Myoseverin B; D-43411 (Zentaris, also known as D-81862);
A-289099 (Abbott); A-318315 (Abbott); HTI-286 (also known as
SPA-110, trifluoroacetate salt) (Wyeth); D-82317 (Zentaris);
D-82318 (Zentaris); SC-12983 (NCl); Resverastatin phosphate sodium;
BPR-0Y-007 (National Health ResearchInstitutes); SSR-250411
(Sanofi); Combretastatin A4; and analogs and derivatives
thereof.
[0138] Taxol.RTM., also referred to as "Paclitaxel", is a
well-known anti-cancer drug which acts by enhancing and stabilizing
microtubule formation. Many analogs of Taxol.RTM. are known,
including taxotere. Taxotere is also referred to as "Docetaxol".
The structures of other Taxol.RTM. analogs are shown in below (and
in U.S. application Ser. No. 11/157,213 the entire contents of
which are incorporated herein by reference):
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021##
[0139] These compounds have the basic taxane skeleton as a common
structure feature and have also been shown to have the ability to
arrest cells in the G2-M phases due to stabilization of
microtubules. Thus, a wide variety of substituents can decorate the
taxane skeleton without adversely affecting biological activity. It
is also apparent that zero, one or both of the cyclohexane rings of
a Taxol.RTM. analog can have a double bond at the indicated
positions. For clarity purposes, the basic taxane skeleton is shown
below in Structural Formula (X):
##STR00022##
Double bonds have been omitted from the cyclohexane rings in the
taxane skeleton represented by Structural Formula (X). The basic
taxane skeleton can include zero or one double bond in one or both
cyclohexane rings, as indicated in Structural Formulas (XI) and
(XII) below. A number of atoms have also been omitted from
Structural Formula (X) to indicate sites in which structural
variation commonly occurs among Taxol.RTM. analogs. For example,
substitution on the taxane skeleton with simply an oxygen atom
indicates that hydroxyl, acyl, alkoxy or another oxygen-bearing
substituent is commonly found at the site. These and other
substitutions on the taxane skeleton can be made without losing the
ability to enhance and stabilize microtubule formation. Thus, the
term "taxol analog" is defined herein to mean a compound which has
the basic taxol skeleton and which promotes microtubule formation.
Taxol.RTM. analogs may be formulated as a nanoparticle colloidal
composition to improve the infusion time and to eliminate the need
to deliver the drug with Cremophor which causes hypersensitivity
reactions in some patients. An example of a Taxol.RTM. analog
formulated as a nanoparticle colloidal composition is ABI-007 which
is a nanoparticle colloidal composition of protein-stabilized
paclitaxel that is reconstituted in saline.
[0140] Typically, the Taxol.RTM. analogs used herein are
represented by Structural Formula (XI) or (XII):
##STR00023##
R.sub.10 is a lower alkyl group, a substituted lower alkyl group, a
phenyl group, a substituted phenyl group, --SR.sub.19, --NHR.sub.19
or --OR.sub.19.
[0141] R.sub.11 is a lower alkyl group, a substituted lower alkyl
group, an aryl group or a substituted aryl group.
[0142] R.sub.12 is --H, --OH, lower alkyl, substituted lower alkyl,
lower alkoxy, substituted lower alkoxy, --O--C(O)-(lower alkyl),
--O--C(O)-(substituted lower alkyl), --O--CH.sub.2--O-(lower
alkyl)-S--CH.sub.2--O-(lower alkyl).
[0143] R.sub.13 is --H, --CH.sub.3, or, taken together with
R.sub.14, --CH.sub.2--.
[0144] R.sub.14 is --H, --OH, lower alkoxy, --O--C(O)-(lower
alkyl), substituted lower alkoxy, --O--C(O)-(substituted lower
alkyl), --O--CH.sub.2--O--P(O)(OH).sub.2, --O--CH.sub.2--O-(lower
alkyl), --O--CH.sub.2--S-(lower alkyl) or, taken together with
R.sub.20, a double bond.
R.sub.15 --H, lower acyl, lower alkyl, substituted lower alkyl,
alkoxymethyl, alkthiomethyl, --OC(O)--O(lower alkyl),
--OC(O)--O(substituted lower alkyl), --OC(O)--NH(lower alkyl) or
--OC(O)--NH(substituted lower alkyl).
[0145] R.sub.16 is phenyl or substituted phenyl.
[0146] R.sub.17 is --H, lower acyl, substituted lower acyl, lower
alkyl, substituted, lower alkyl, (lower alkoxy)methyl or (lower
alkyl)thiomethyl.
[0147] R.sub.18 --H, --CH.sub.3 or, taken together with R.sub.17
and the carbon atoms to which R.sub.17 and R.sub.18 are bonded, a
five or six membered a non-aromatic heterocyclic ring.
[0148] R.sub.19 is a lower alkyl group, a substituted lower alkyl
group, a phenyl group, a substituted phenyl group.
[0149] R.sub.20 is --H or a halogen.
[0150] R.sub.21 is --H, lower alkyl, substituted lower alkyl, lower
acyl or substituted lower acyl.
[0151] Preferably, the variables in Structural Formulas (XI) and
(XII) are defined as follows: R.sub.10 is phenyl, tert-butoxy,
--S--CH.sub.2--CH--(CH.sub.3).sub.2, --S--CH(CH.sub.3).sub.3,
--S--(CH.sub.2).sub.3CH.sub.3, --O--CH(CH.sub.3).sub.3,
--NH--CH(CH.sub.3).sub.3, --CH.dbd.C(CH.sub.3).sub.2 or
para-chlorophenyl; R.sub.11 is phenyl,
(CH.sub.3).sub.2CHCH.sub.2--, -2-furanyl, cyclopropyl or
para-toluoyl; R.sub.12 is --H, --OH, CH.sub.3CO-- or
--(CH.sub.2).sub.2--N-morpholino; R.sub.13 is methyl, or, R.sub.13
and R.sub.14, taken together, are --CH.sub.2--;
[0152] R.sub.14 is --H, --CH.sub.2SCH.sub.3 or
--CH.sub.2--O--P(O)(OH).sub.2; R.sub.15 is CH.sub.3CO--;
[0153] R.sub.16 is phenyl; R.sub.17 --H, or, R.sub.17 and R.sub.18,
taken together, are --O--CO--O--;
[0154] R.sub.18 is --H; R.sub.20 is --H or --F; and R.sub.21 is
--H, --C(O)--CHBr--(CH.sub.2).sub.13--CH.sub.3 or
--C(O)--(CH.sub.2).sub.14--CH.sub.3;
--C(O)--CH.sub.2--CH(OH)--COOH,
--C(O)--CH.sub.2--O--C(O)--CH.sub.2CH(NH.sub.2)--CONH.sub.2,
--C(O)--CH.sub.2--O--CH.sub.2CH.sub.2OCH.sub.3 or
--C(O)--O--C(O)--CH.sub.2CH.sub.3.
[0155] A Taxol.RTM. analog can also be bonded to or be pendent from
a pharmaceutically acceptable polymer, such as a polyacrylamide.
One example of a polymer of this type is shown in US Application
Publication No. 2006/0135595. The term "taxol analog", as it is
used herein, includes such polymers.
[0156] In some embodiments, Taxol.RTM. analogs have a taxane
skeleton represented by Structural Formula IX, wherein Z is O, S,
or NR. Taxol.RTM. analogs that have the taxane skeleton shown in
Structural Formula IX can have various substituents attached to the
taxane skeleton and can have a double bond in zero, one or both of
the cyclohexane rings as shown, for example in FIGS. 3-23.
##STR00024##
[0157] Various Taxol.RTM. analogs and Taxol.RTM. formulations are
described in Hennenfent et al. (2006) Annals of Oncology
17:735-749; Gradishar (2006) Expert Opin. Pharmacother.
7(8):1041-53; Attard et al. (2006) Pathol Biol 54(2):72-84;
Straubinger et al. (2005) Methods Enzymol. 391:97-117; Ten Tije et
al. (2003) Clin Pharmacokinet. 42(7):665-85; and Nuijen et al.
(2001) Invest New Drugs. 19(2):143-53, the entire teachings of
which are incorporated herein by reference.
[0158] In a particular embodiment, the present invention is a
method of treating a subject with a proliferative disease, such as
cancer, comprising administering to the subject an effective amount
of a bis(thiohydrazide amides) in combination with hyperthermia
treatment, and an effective amount of a microtubulin stabilizer
(e.g., taxol or taxotere). In one embodiment, renal cell carcinoma
and melanoma are treated with the disclosed methods.
[0159] In a particular embodiment, the present invention is a
method of treating a subject with a proliferative disease, such as
cancer, comprising administering to the subject an effective amount
of a bis(thiohydrazide amides), in combination with hyperthermia
treatment, an effective amount of a microtubulin stabilizer (e.g.,
taxol or taxotere) and an effective amount of another anti-cancer
agent as described herein. In one embodiment, renal cell carcinoma
and melanoma are treated with the disclosed methods.
[0160] In a particular embodiment, the present invention is a
method of treating a subject with a proliferative disease, such as
cancer, comprising administering to the subject an effective amount
of a bis(thiohydrazide amides), in combination with radiotherapy,
and an effective amount of a microtubulin stabilizer (e.g., taxol
or taxotere). In one embodiment, renal cell carcinoma and melanoma
are treated with the disclosed methods.
[0161] In a particular embodiment, the present invention is a
method of treating a subject with a proliferative disease, such as
cancer, comprising administering to the subject an effective amount
of a bis(thiohydrazide amides), in combination with radiotherapy,
an effective amount of a microtubulin stabilizer (e.g., taxol or
taxotere) and an effective amount of another anti-cancer agent as
described herein. In one embodiment, renal cell carcinoma and
melanoma are treated with the disclosed methods.
[0162] In a particular embodiment, the anti-cancer agent is
selected from the group consisting of dacarbazine (brand name
DTIC), temozolomide (brand name Temodar), cisplatin, carmustine
(also known as BCNU), fotemustine, vindesine, vincristine sorafenib
and bleomycin. In another particular embodiment, the anti-cancer
agent is selected from the group carboplatin, tamoxifen and
Nolvadex. In another particular embodiment the anti-cancer agent is
selected from the group vinablastine, G-CSF and navelbine. In
another particular embodiment the anti-cancer agent is selected
from the combinations of drugs selected from dacarbazine and G-CSF
or carboplatin and sorafenib. In another particular embodiment the
anti-cancer agent is selected from the combinations of drugs
selected from dacarbazine and Granulocyte colony-stimulating factor
(G-CSF), Carboplatin and Sorafenib, dacarbazine, carmustine
cisplatin, and tamoxifen, or cisplatin, vinblastine, and
dacarbazine.
[0163] In certain embodiments the present invention is directed to
administering to a subject with an immunosensitive cancer, in
particular melanoma, with an effective amount of a
bis(thiohydrazide amide), in combination with hyperthermia or
radiotherapy, an effective amount of an immunotherapy and
optionally one or more additional anti-cancer agents, wherein the
immunotherapy and anti-cancer agent are selected from Interleukin2
(IL2; Proleukin), Interferon (IFN alfa-2b, IFN), IFN (interferon)
in combination, MDX 010, MDX-1379, Dacarbazide, Genasense,
Cisplatin, vinblastine, Carmustine, dacarbazine, or Nolvadex, or
selected from the following groups:
Biologic Response Modifiers:
Interleukin2 (IL2; Proleukin)
[0164] Interferon (IFN alfa-2b, IFN)
Biochemotherapy:
[0165] IFN (interferon)
MDX 010+IL-2
MDX010+MDX-1379
Dacarbazide+Genasense
Dacarbazide+Cisplatin+IFN
Dacarbazide+Cisplatin+IFN+IL-2
[0166] Cisplatin+vinblastine+dacarbazine+IL-2+IFN
Carmustine+dacarbazine+cisplatin+Nolvadex+IL-2+IFN.
[0167] In certain embodiments the present invention is directed to
administering to a subject with an immunosensitive cancer, in
particular renal cell carcinoma, with an effective amount of a
bis(thiohydrazide amide), in combination with hyperthermia or
radiotherapy, an effective amount of an immunotherapy and
optionally one or more additional anti-cancer agents, wherein the
immunotherapy and anti-cancer agent are selected from of rapamycin,
geldenamyci, 17-allylamino, 17-demethoxygeldanamycin, histone
deacetylase inhibitors, topoisomerase I inhibitors, thioredoxin 1
inhibitors, mictotubule disruptors, Epothilone, EP0906, an
allogenic bone marrow stem cell transplantation, allogenic
hematopoietic stem cell transplantation, PTK 787, SU 11248 bey
43-9006, medroxyprogestterone, ABX-EGF, imatinib mesylate, ZD1839,
SU5416, bortezomib (PS-341), BAY 59-8862, HSPPC-96, thalidomide
ABT-510, CCI-779 or RAD-001, or combinations of bevacizumab and
thalidomide, or combinations of thalidomide and IFN-.alpha., or
combinations of FUNIL and thalidomide, or combinations of CAPE and
IFN-.alpha., or combinations of gemcitabine (GEM) and capecitabine
(CAPE), or combinations of thalidomide and IL-2, and thalidomide,
or combinations of HSPPC-96 and IL-2 or a combination of
bevacizumab, IL-2, interferon and optionally an additional
anti-cancer agent, or a combination of IFN-.alpha. and IL-2.
[0168] In certain embodiments the present invention is directed to
administering to a subject with an immuno sensitive cancer, in
particular renal cell carcinoma, with an effective amount of a
bis(thiohydrazide amide), in combination with hyperthermia or
radiotherapy, and an effective amount of an immunotherapy which is
a combination of IFN-.alpha. and IL-2.
[0169] The above methods disclosed in the immediately preceding
paragraph are particularly advantageous in treating melanoma.
[0170] Numerous non-cancer diseases involve excessive or
hyperproliferative cell growth, termed hyperplasia. As used herein,
the terms "proliferative disorder", "hyperproliferative disorder,"
and "cell proliferation disorder" are used interchangeably to mean
a disease or medical condition involving pathological growth of
cells. Such disorders include cancer.
[0171] Non-cancerous proliferative disorders include smooth muscle
cell proliferation, systemic sclerosis, cirrhosis of the liver,
adult respiratory distress syndrome, idiopathic cardiomyopathy,
lupus erythematosus, retinopathy, e.g., diabetic retinopathy or
other retinopathies, cardiac hyperplasia, reproductive system
associated disorders such as benign prostatic hyperplasia and
ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis,
harmatomas, lymphangiomatosis, sarcoidosis, desmoid tumors and the
like.
[0172] Smooth muscle cell proliferation includes proliferative
vascular disorders, for example, intimal smooth muscle cell
hyperplasia, restenosis and vascular occlusion, particularly
stenosis following biologically- or mechanically-mediated vascular
injury, e.g., vascular injury associated with balloon angioplasty
or vascular stenosis. Moreover, intimal smooth muscle cell
hyperplasia can include hyperplasia in smooth muscle other than the
vasculature, e.g., hyperplasia in bile duct blockage, in bronchial
airways of the lung in asthma patients, in the kidneys of patients
with renal interstitial fibrosis, and the like.
[0173] Non-cancerous proliferative disorders also include
hyperproliferation of cells in the skin such as psoriasis and its
varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris,
and hyperproliferative variants of disorders of keratinization
(e.g., actinic keratosis, senile keratosis), scleroderma, and the
like.
[0174] Cancers which can be treated by the methods of the present
invention include, but are not limited to, human sarcomas and
carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma,
chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,
endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,
synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,
rhabdomyosarcoma, colon carcinoma, colorectal cancer, anal
carcinoma, esophageal cancer, gastric cancer, hepatocellular
cancer, bladder cancer, endometrial cancer, pancreatic cancer,
breast cancer, ovarian cancer, prostate cancer, stomach cancer,
atrial myxomas, squamous cell carcinoma, basal cell carcinoma,
adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,
thyroid and parathyroid neoplasms, papillary carcinoma, papillary
adenocarcinomas, cystadenocarcinoma, medullary carcinoma,
bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct
carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'
tumor, cervical cancer, testicular tumor, lung carcinoma, small
cell lung carcinoma, non-small-cell lung cancer, bladder carcinoma,
epithelial carcinoma, glioma, pituitary neoplasms, astrocytoma,
medulloblastoma, craniopharyngioma, ependymoma, pinealoma,
hemangioblastoma, acoustic neuroma, schwannomas, oligodendroglioma,
meningioma, spinal cord tumors, melanoma, neuroblastoma,
pheochromocytoma, Types 1-3 endocrine neoplasia, retinoblastoma;
leukemias, e.g., acute lymphocytic leukemia and acute myelocytic
leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic
and erythroleukemia); chronic leukemia (chronic myelocytic
(granulocytic) leukemia and chronic lymphocytic leukemia); and
polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's
disease), multiple myeloma, Waldenstrobm's macroglobulinemia, and
heavy chain disease.
[0175] Other examples of leukemias include acute and/or chronic
leukemias, e.g., lymphocytic leukemia (e.g., as exemplified by the
p388 (murine) cell line), large granular lymphocytic leukemia, and
lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia
(e.g., as exemplified by the CEM, Jurkat, and HSB-2 (acute), YAC-1
(murine) cell lines), T-lymphocytic leukemia, and T-lymphoblastic
leukemia; B cell leukemia (e.g., as exemplified by the SB (acute)
cell line), and B-lymphocytic leukemia; mixed cell leukemias, e.g.,
B and T cell leukemia and B and T lymphocytic leukemia; myeloid
leukemias, e.g., granulocytic leukemia, myelocytic leukemia (e.g.,
as exemplified by the HL-60 (promyelocyte) cell line), and
myelogenous leukemia (e.g., as exemplified by the K562 (chronic)
cell line); neutrophilic leukemia; eosinophilic leukemia; monocytic
leukemia (e.g., as exemplified by the THP-1 (acute) cell line);
myelomonocytic leukemia; Naegeli-type myeloid leukemia; and
nonlymphocytic leukemia. Other examples of leukemias are described
in Chapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed.,
Williams & Williams (1992) and Section 36 of Holland Frie
Cancer Medicine 5th Ed., Bast et al. Eds., B.C. Decker Inc. (2000).
The entire teachings of the preceding references are incorporated
herein by reference.
[0176] In one embodiment, the methods of the present invention
include treating cancers including, but not limited to, non-solid
tumors such as multiple myeloma, T-leukemia (e.g., as exemplified
by Jurkat and CEM cell lines); B-leukemia (e.g., as exemplified by
the SB cell line); promyelocytes (e.g., as exemplified by the HL-60
cell line); uterine sarcoma (e.g., as exemplified by the MES-SA
cell line); monocytic leukemia (e.g., as exemplified by the THP-1
(acute) cell line); and lymphoma (e.g., as exemplified by the U937
cell line).
[0177] Immunosensitive cancers respond to immunotherapy, i.e.,
agents that stimulate the immune system. Examples of
immunosensitive cancers include, renal cell carcinoma, melanoma,
multiple myeloma, myeloma, lymphoma, non-small-cell lung cancer,
bladder cancer, prostate cancer, squamous cell carcinoma, basal
cell carcinoma, fibrosarcoma, malignant brain tumors, Kaposi's
Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia.
[0178] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of a proliferative disease,
such as cancer, in subjects who have been treated for the
proliferative disease, such as cancer, comprising administering an
effective amount of
##STR00025##
[0179] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0180] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of a proliferative disease,
such as cancer, in subjects who have been treated for the
proliferative disease, such as cancer, comprising administering an
effective amount of
##STR00026##
[0181] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0182] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of an immunosensitive cancer
selected from the group consisting of renal cell carcinoma,
melanoma, multiple myeloma, myeloma, lymphoma, non-small-cell lung
cancer, bladder cancer, prostate cancer, squamous cell carcinoma,
basal cell carcinoma, fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia in subjects who have been treated for the cancer,
comprising administering an effective amount of
##STR00027##
[0183] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0184] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of an immunosensitive cancer
selected from the group consisting of renal cell carcinoma,
melanoma, multiple myeloma, myeloma, lymphoma, non-small-cell lung
cancer, bladder cancer, prostate cancer, squamous cell carcinoma,
basal cell carcinoma, fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia in subjects who have been treated for the cancer,
comprising administering an effective amount of
##STR00028##
[0185] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0186] In certain embodiments, the present invention is directed to
treating a subject with a proliferative disease, such as cancer,
comprising administering an effective amount of
##STR00029##
[0187] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0188] In certain embodiments, the present invention is directed to
treating a subject with a proliferative disease, such as cancer,
comprising administering an effective amount of
##STR00030##
[0189] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0190] In certain embodiments, the present invention is directed to
treating a subject with an immunosensitive cancer selected from the
group consisting of renal cell carcinoma, melanoma, multiple
myeloma, myeloma, lymphoma, non-small-cell lung cancer, bladder
cancer, prostate cancer, squamous cell carcinoma, basal cell
carcinoma, fibrosarcoma, malignant brain tumors, Kaposi's Sarcoma,
chronic myelogenous leukemia (CML) and hairy cell leukemia,
comprising administering an effective amount of
##STR00031##
[0191] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0192] In certain embodiments, the present invention is directed to
treating a subject with an immunosensitive cancer selected from the
group consisting of renal cell carcinoma, melanoma, multiple
myeloma, myeloma, lymphoma, non-small-cell lung cancer, bladder
cancer, prostate cancer, squamous cell carcinoma, basal cell
carcinoma, fibrosarcoma, malignant brain tumors, Kaposi's Sarcoma,
chronic myelogenous leukemia (CML) and hairy cell leukemia,
comprising administering an effective amount of
##STR00032##
[0193] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0194] In another embodiment, the disclosed method involves
treating a subject with melanoma. Melanoma, can be divided into
five main subgroups:
[0195] i) Congenital Nevus: which is congenital and not
malignant.
[0196] ii) Lentigo Maligna (Hutchinsons Freckle): which is a form
of melanoma more common among the elderly population. These lesions
may grow for years as an in-situ tumor before developing the more
aggressive vertical growth phase. This type of melanoma is found
most often in the damaged skin on the face, ears, arms, and upper
trunk.
[0197] iii) Superficial Spreading Malignant Melanoma: is generally
the most common form accounting for approximately 65% of diagnosed
melanoma. The cancer presumably begins at one focus in the skin at
the dermo-epidermal junction. It initially grows in a horizontal
plane, along, just above and below the dermo-epidermal junction.
This is referred to as the "radial" growth phase of melanoma and is
clinically macular or only slightly elevated.
[0198] This melanoma travels along the top layer of the skin for a
fairly long time before penetrating more deeply. The melanoma can
be seen almost anywhere on the body, but is most likely to occur on
the trunk in men, the legs in women, and the upper back in both.
This type of melanoma is mainly found in the younger
population.
[0199] iv) Acral Lentiginous Malignant Melanoma: as with
superficial spreading malignant melanoma, acral lentiginous
malignant melanoma also spreads superficially before penetrating
more deeply. It is quite different from the others, though, as it
usually appears as a black or brown discoloration under the nails
or on the soles of the feet or palms of the hands. This type of
melanoma is the most common melanoma in African-Americans and
Asians, and the least common among Caucasians.
[0200] v) Nodular Malignant Melanoma: is a much less common form of
melanoma. Unlike the other types, nodular melanoma, is usually
invasive at the time it is first diagnosed. The malignancy is
recognized when it becomes a bump. In this tumor, there is
presumably no horizontal growth phase. The depth of the lesion
appears to correlate with the prognosis of the subject, and nodular
melanoma is less often amenable to definitive treatment than is the
superficial spreading variety.
[0201] The methods of the present invention encompass treating all
of the subgroups of melanoma defined above.
[0202] Melanoma can further be divided into four different stages,
which are divided based on the progression of the disease:
[0203] Stage I
[0204] Cancer is found in the outer layer of the skin (epidermis)
and/or the upper part of the inner layer of skin (dermis), but it
has not spread to nearby lymph nodes. The tumor is less than 1.5
millimeters ( 1/16 of an inch) thick.
[0205] Stage III
[0206] The tumor is 1.5 millimeters to 4 millimeters (less than 1/6
of an inch) thick. It has spread to the lower part of the inner
layer of skin (dermis), but not into the tissue below the skin or
into nearby lymph nodes.
[0207] Stage III
[0208] Any of the following mean that the tumor is stage III:
[0209] The tumor is more than 4 millimeters (approximately 1/6 of
an inch) thick.
[0210] The tumor has spread to the body tissue below the skin.
[0211] There are additional tumor growths within one inch of the
original tumor (satellite tumors).
[0212] The tumor has spread to nearby lymph nodes or there are
additional tumor growths (satellite tumors) between the original
tumor and the lymph nodes in the area
[0213] Stage IV
[0214] The tumor has spread to other organs or to lymph nodes far
away from the original tumor.
[0215] In another embodiment, the disclosed method involves
treating a subject with renal cell carcinoma.
[0216] Renal cell carcinoma is the most common type of kidney
cancer. It accounts for more than 90% of malignant kidney tumors.
Renal cell carcinoma begins small and grows larger over time.
Although renal cell carcinoma usually grows as a single mass within
the kidney, a kidney may contain more than 1 tumor. Sometimes
tumors may be found in both kidneys at the same time. Some renal
cell carcinomas are noticed only after they have become quite
large; most are found before they metastasize to other organs
through the bloodstream or lymph vessels. Like most cancers, renal
cell carcinoma is difficult to treat once it has metastasized.
There are five main types of renal cell carcinoma: clear cell,
papillary, chromophobe, collecting duct, and "unclassified."
[0217] When viewed under a microscope, the individual cells that
make up clear cell renal cell carcinoma appear very pale or clear.
This is the most common form of renal cell carcinoma. About 80% of
people with renal cell carcinoma have this kind of cancer.
[0218] Papillary renal cell carcinoma is the second most common
type--about 10% to 15% of people have this kind. These cancers form
little finger-like projections (called papillae) in some, if not
most, of the tumor. Some doctors call these cancers chromophilic
because the cells take up certain dyes used in preparing the tissue
to be viewed under the microscope, causing them to appear pink.
[0219] Chromophobe renal carcinoma is the third most common
type--accounting for about 5% of cases. The cells of these cancers
are also pale, like the clear cells, but are much larger and have
certain other features that can be recognized.
[0220] The fourth type, collecting duct renal carcinoma, is very
rare. The major feature is that the cancer cells can form irregular
tubes.
[0221] About 5% of renal cancers are unclassified because their
appearance does not fit into any of the other categories.
[0222] Renal cell cancers are usually divided into four stages. The
stage describes the cancer's size and how far it has spread beyond
the kidney.
[0223] The Stage are generally defined below:
[0224] Stage I
[0225] The tumor is 7 cm or smaller and limited to the kidney.
There is no spread to lymph nodes or distant organs.
[0226] Stage II:
[0227] The tumor is larger than 7 cm but is still limited to the
kidney. There is no spread to lymph nodes or distant organs.
[0228] Stage III:
[0229] This includes:
[0230] any tumor that has spread to 1 nearby lymph node but not to
more than 1 lymph node or other organs; and/or
[0231] tumors that have not spread to lymph nodes or distant organs
but have spread to the adrenal glands, to fatty tissue around the
kidney, and/or have grown into the large vein (vena cava) leading
from the kidney to the heart.
[0232] Stage IV:
[0233] This includes:
[0234] any cancers that have spread directly through the fatty
tissue and beyond Gerota fascia, the fibrous tissue that surrounds
the kidney; and/or
[0235] any cancer that has spread to more than 1 lymph node near
the kidney, or to any lymph node distant from the kidney, or to any
distant organs such as the lungs, bone, or brain.
[0236] The disclosed methods include treating all five types of
renal cell carcinoma in all four stages of disease progression as
defined immediately above.
[0237] The first line treatment for renal cell carcinoma, when
detected at an early stage, is often to surgically remove the
cancer, for example, by radial nephrectomy. However, in many cases,
as many as 20 or 30% of subjects develop metastatic (Stage III or
IV) disease. For those subjects with metastatic (Stage III and IV)
renal cell carcinoma, the prognosis is bleak.
[0238] In certain embodiments, the present invention is directed to
treating renal cell carcinoma in a subject, comprising
administering an effective amount of
##STR00033##
[0239] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0240] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of
##STR00034##
[0241] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0242] In certain embodiments, the present invention is directed to
treating renal cell carcinoma in a subject, comprising
administering an effective amount of
##STR00035##
[0243] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0244] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of
##STR00036##
[0245] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0246] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of a
bis(thiohydrazide amide) described herein, in combination with
hyperthermia, and optionally a microtubulin stabilizer, such as,
taxol or taxotere.
[0247] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of a
bis(thiohydrazide amide) described herein, in combination with
hyperthermia, and an effective amount of a microtubulin stabilizer,
such as, taxol or taxotere.
[0248] In certain embodiments, the present invention is directed to
treating subjects with Stage III and IV renal cell carcinoma with
an effective amount of a bis(thiohydrazide amide) described herein,
in combination with hyperthermia, and an effective amount of a
microtubulin stabilizer, such as, taxol or taxotere.
[0249] In certain embodiments, the present invention is directed to
treating subjects with Stage 1V renal cell carcinoma with an
effective amount of a bis(thiohydrazide amide) described herein, in
combination with hyperthermia, and an effective amount microtubulin
stabilizer, such as, taxol or taxotere.
[0250] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of a
bis(thiohydrazide amide) described herein, in combination with
radiotherapy, and optionally a microtubulin stabilizer, such as,
taxol or taxotere.
[0251] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of a
bis(thiohydrazide amide) described herein, in combination with
radiotherapy, and an effective amount of a microtubulin stabilizer,
such as, taxol or taxotere.
[0252] In certain embodiments, the present invention is directed to
treating subjects with Stage III and IV renal cell carcinoma with
an effective amount of a bis(thiohydrazide amide) described herein,
in combination with radiotherapy, and an effective amount of a
microtubulin stabilizer, such as, taxol or taxotere.
[0253] In certain embodiments, the present invention is directed to
treating subjects with Stage IV renal cell carcinoma with an
effective amount of a bis(thiohydrazide amide) described herein, in
combination with radiotherapy, and an effective amount microtubulin
stabilizer, such as, taxol or taxotere.
[0254] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of
##STR00037##
[0255] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0256] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of
##STR00038##
[0257] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and an effective amount of a microtubulin stabilizer, such as,
taxol or taxotere.
[0258] In certain embodiments, the present invention is directed to
treating subjects with Stage III and IV renal cell carcinoma with
an effective amount of
##STR00039##
[0259] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with hyperthermia,
and an effective amount of a microtubulin stabilizer, such as,
taxol or taxotere.
[0260] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of
##STR00040##
[0261] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and optionally a microtubulin stabilizer, such as, taxol or
taxotere.
[0262] In certain embodiments, the present invention is directed to
preventing or delaying the recurrence of renal cell carcinoma in
subjects who have been treated for Stage I, II, or III renal cell
carcinoma, comprising administering an effective amount of
##STR00041##
[0263] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and an effective amount of a microtubulin stabilizer, such as,
taxol or taxotere.
[0264] In certain embodiments, the present invention is directed to
treating subjects with Stage III and IV renal cell carcinoma with
an effective amount of
##STR00042##
[0265] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof, in combination with radiotherapy,
and an effective amount of a microtubulin stabilizer, such as,
taxol or taxotere.
[0266] In another embodiment, the disclosed method involves
treating subjects whose cancer has become "multi-drug
resistant".
[0267] In a particular embodiment the disclosed method involves
treating immunosensitive cancers, including, but not limited to,
renal cell carcinoma, melanoma, multiple myeloma, myeloma,
lymphoma, non-small-cell lung cancer, squamous cell carcinoma,
basal cell carcinoma, fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, hairy cell leukemia, ovarian cancer, breast
cancer, colorectal cancer, lung cancer, leukemia, prostate cancer,
pancreatic cancer, head and neck cancer, and liver cancer.
Preferably, the immunosensitive cancer is selected from the group
Renal cell carcinoma, Melanoma (including superficial spreading
SSM, nodular NM, acral lentiginous ALM, lentigo maligna LMM also
called Hutchinson's Freckle), Multiple myeloma, Myeloma, Lymphoma,
Non-small-cell lung cancer, bladder cancer, prostate cancer,
Squamous cell carcinoma, Basal cell carcinoma, Fibrosarcoma,
malignant brain tumors, Kaposi's Sarcoma, chronic myelogenous
leukemia (CML) and hairy cell leukemia.
[0268] In one preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a cancer vaccine.
[0269] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a tumor cell vaccine.
[0270] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a viral vaccine.
[0271] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of an autologous tumor cell vaccine.
[0272] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of an allogeneic tumor cell vaccine.
[0273] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a dendritic cell vaccine.
[0274] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a antigen vaccine.
[0275] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a anti-idiotype vaccine.
[0276] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a DNA vaccine.
[0277] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a Tumor-Infiltrating Lymphocyte (TIL)
Vaccine with Interleukin-2 (IL-2).
[0278] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a Lymphokine-Activated Killer (LAK) Cell
Therapy.
[0279] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Rituximab (Rituxan).
[0280] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Trastuzumab (Herceptin).
[0281] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Alemtuzumab (Campath).
[0282] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of and Cetuximab (Erbitux).
[0283] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Bevacizumab (Avastin).
[0284] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a Radiolabeled antibody Ibritumomab tiuxetan
(Zevalin).
[0285] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a radiolabeled antibody Tositumomab
(Bexxar).
[0286] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a immunotoxin Gemtuzumab ozogamicin
(Mylotarg).
[0287] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of BL22.
[0288] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of OncoScint.
[0289] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of ProstaScint.
[0290] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of denileukin diftitox (Ontak).
[0291] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a granulocyte-macrophage colony-stimulating
factor (GM-CSF).
[0292] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of granulocyte-colony stimulating factor
(G-CSF).
[0293] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of macrophage inflammatory protein
(MIP)-1-alpha.
[0294] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of an interleukin.
[0295] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-1.
[0296] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-2.
[0297] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-4.
[0298] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-6.
[0299] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-7.
[0300] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-12.
[0301] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-15.
[0302] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-18.
[0303] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-21.
[0304] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IL-27.
[0305] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a tumor necrosis factors.
[0306] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of TNF-alpha.
[0307] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of an interferon.
[0308] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IFN-alpha.
[0309] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IFN-beta.
[0310] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of IFN-gamma.
[0311] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of aluminum hydroxide (alum).
[0312] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Bacille Calmette-Guerin (BCG).
[0313] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Keyhole limpet hemocyanin (KLH).
[0314] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Incomplete Freund's adjuvant (IFA).
[0315] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of QS-21.
[0316] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of DETOX.
[0317] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Levamisole.
[0318] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of Dinitrophenyl (DNP).
[0319] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a tumor-infiltrating lymphocyte.
[0320] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a human monoclonal antibody to ganglioside
antigens.
[0321] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a polyvalent antigen vaccine.
[0322] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a combination of IL-2 with IFN-alpha.
[0323] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a combination of an interleukin with a
cytokine.
[0324] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of combination of IL-12 and TNF-alpha.
[0325] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a combination of BCG with a melanoma vaccine
and optionally another immunotherapy as described herein.
[0326] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a combination of IL-2, interferon and an
anti-cancer agent as described herein.
[0327] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a combination of a tumor cell vaccine with
BCG.
[0328] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a combination of a DNA vaccine and
tumor-infiltrating lymphocytes.
[0329] In another preferred embodiment the present invention is a
method of treating an immunosensitive cancer selected from the
group Renal cell carcinoma, Melanoma (including superficial
spreading SSM, nodular NM, acral lentiginous ALM, lentigo maligna
LMM also called Hutchinson's Freckle), Multiple myeloma, Myeloma,
Lymphoma, Non-small-cell lung cancer, Squamous cell carcinoma,
Basal cell carcinoma, Fibrosarcoma, malignant brain tumors,
Kaposi's Sarcoma, chronic myelogenous leukemia (CML) and hairy cell
leukemia, comprising administering an effective amount of a
bis(thiohydrazide amide) as described herein in combination with
hyperthermia or radiotherapy and further comprising administering
an effective amount of a combination of a chimeric bispecific
G250/anti-CD3 monoclonal antibody.
[0330] In all of the above preceding paragraphs of preferred
embodiments taxol or taxotere are also optionally administered.
[0331] In one embodiment of the present invention the
bis(thiohydrazide amides) described herein and the other anticancer
therapies described herein can be administered to a subject in the
form of a pharmaceutical composition.
[0332] As used herein, a "pharmaceutical composition" can be a
formulation containing the disclosed compounds, in a form suitable
for administration to a subject. The pharmaceutical composition can
be in bulk or in unit dosage form. The unit dosage form can be in
any of a variety of forms, including, for example, a capsule, an IV
bag, a tablet, a single pump on an aerosol inhaler, or a vial. The
quantity of active ingredient (i.e., a formulation of the disclosed
compound or salts thereof) in a unit dose of composition can be an
effective amount and can be varied according to the particular
treatment involved. It may be appreciated that it can be necessary
to make routine variations to the dosage depending on the age and
condition of the patient. The dosage can also depend on the route
of administration. Examples of suitable dosages are those described
in PCT/US2006/014531 filed 13 Apr. 2006, titled Combination Cancer
Therapy With Bis[Thiohydrazide] Amide Compounds, the entire
contents of which are incorporated herein by reference. A variety
of routes are contemplated, including topical, oral, pulmonary,
rectal, vaginal, parenternal, including transdermal, subcutaneous,
intravenous, intramuscular, intraperitoneal and intranasal.
[0333] The compounds described herein, and the pharmaceutically
acceptable salts thereof can be used in pharmaceutical preparations
in combination with a pharmaceutically acceptable carrier or
diluent. Suitable pharmaceutically acceptable carriers include
inert solid fillers or diluents and sterile aqueous or organic
solutions. The compounds can be present in such pharmaceutical
compositions in amounts sufficient to provide the desired dosage
amount in the range described herein. Techniques for formulation
and administration of the disclosed compounds of the invention can
be found in Remington: the Science and Practice of Pharmacy,
19.sup.th edition, Mack Publishing Co., Easton, Pa. (1995). The
bis(thio-hydrazide amide) disclosed herein can be prepared by the
methods described in U.S. Provisional Patent No. 60/708,977 filed
16 Aug. 2005, titled Bis(Thio-Hydrazide Amide) Formulation, the
entire teachings of which is incorporated herein by reference.
[0334] In one embodiment the bis(thio hydrazide amide) described
herein is added to a solution of Taxol in Cremophor.RTM.. In one
embodiment, Taxol is 6 mg/mL and the bis(thiohydrazid amide) (e.g.,
compound (1) is 16 mg/L in the Cremophor.RTM. solution. Optionally,
the solution is then diluted with a saline solution Specifically,
for Intravenous Administration: Taxol is diluted prior to infusion,
for example, Taxol is diluted in 0.9% Sodium Chloride Injection,
USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium
Chloride Injection, USP, or 5% Dextrose in Ringer's Injection to a
final concentration of 0.3 to 1.2 mg/mL.
[0335] For oral administration, the disclosed compounds or salts
thereof can be combined with a suitable solid or liquid carrier or
diluent to form capsules, tablets, pills, powders, syrups,
solutions, suspensions, or the like.
[0336] The tablets, pills, capsules, and the like can contain from
about 1 to about 99 weight percent of the active ingredient and a
binder such as gum tragacanth, acacias, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch or alginic acid; a lubricant such as
magnesium stearate; and/or a sweetening agent such as sucrose,
lactose or saccharin. When a dosage unit form is a capsule, it may
contain, in addition to materials of the above type, a liquid
carrier such as a fatty oil.
[0337] Various other materials can be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor, and the like.
[0338] For parental administration, the bis(thio-hydrazide) amides
can be combined with sterile aqueous or organic media to form
injectable solutions or suspensions. For example, solutions in
sesame or peanut oil, aqueous propylene glycol and the like can be
used, as well as aqueous solutions of water-soluble
pharmaceutically-acceptable salts of the compounds. Dispersions can
also be prepared in glycerol, liquid polyethylene glycols and
mixtures thereof in oils. Under ordinary conditions of storage and
use, these preparations contain a preservative to prevent the
growth of microorganisms.
[0339] In addition to the formulations previously described, the
compounds may also be formulated as a depot preparation. Suitable
formulations of this type include biocompatible and biodegradable
polymeric hydrogel formulations using crosslinked or water
insoluble polysaccharide formulations, polymerizable polyethylene
oxide formulations, impregnated membranes, and the like. Such long
acting formulations may be administered by implantation or
transcutaneous delivery (for example subcutaneously or
intramuscularly), intramuscular injection or a transdermal patch.
Typically, they can be implanted in, or applied to, the
microenvironment of an affected organ or tissue, for example, a
membrane impregnated with the disclosed compound can be applied to
an open wound or burn injury. Thus, for example, the compounds may
be formulated with suitable polymeric or hydrophobic materials, for
example, as an emulsion in an acceptable oil, or ion exchange
resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.
[0340] For topical administration, suitable formulations may
include biocompatible oil, wax, gel, powder, polymer, or other
liquid or solid carriers. Such formulations may be administered by
applying directly to affected tissues, for example, a liquid
formulation to treat infection of conjunctival tissue can be
administered dropwise to the subject's eye, a cream formulation can
be administer to a wound site, or a bandage may be impregnated with
a formulation, and the like.
[0341] For rectal administration, suitable pharmaceutical
compositions are, for example, topical preparations, suppositories
or enemas.
[0342] For vaginal administration, suitable pharmaceutical
compositions are, for example, topical preparations, pessaries,
tampons, creams, gels, pastes, foams or sprays.
[0343] In addition, the compounds may also be formulated to deliver
the active agent by pulmonary administration, e.g., administration
of an aerosol formulation containing the active agent from, for
example, a manual pump spray, nebulizer or pressurized metered-dose
inhaler. Suitable formulations of this type can also include other
agents, such as antistatic agents, to maintain the disclosed
compounds as effective aerosols.
[0344] The term "pulmonary" as used herein refers to any part,
tissue or organ whose primary function is gas exchange with the
external environment, i.e., O.sub.2/CO.sub.2 exchange, within a
patient. "Pulmonary" typically refers to the tissues of the
respiratory tract. Thus, the phrase "pulmonary administration"
refers to administering the formulations described herein to any
part, tissue or organ whose primary function is gas exchange with
the external environment (e.g., mouth, nose, pharynx, oropharynx,
laryngopharynx, larynx, trachea, carina, bronchi, bronchioles,
alveoli). For purposes of the present invention, "pulmonary" is
also meant to include a tissue or cavity that is contingent to the
respiratory tract, in particular, the sinuses.
[0345] A drug delivery device for delivering aerosols can comprise
a suitable aerosol canister with a metering valve containing a
pharmaceutical aerosol formulation as described and an actuator
housing adapted to hold the canister and allow for drug delivery.
The canister in the drug delivery device has a head space
representing greater than about 15% of the total volume of the
canister. Often, the polymer intended for pulmonary administration
is dissolved, suspended or emulsified in a mixture of a solvent,
surfactant and propellant. The mixture is maintained under pressure
in a canister that has been sealed with a metering valve.
[0346] For nasal administration, either a solid or a liquid carrier
can be used. The solid carrier includes a coarse powder having
particle size in the range of, for example, from about 20 to about
500 microns and such formulation is administered by rapid
inhalation through the nasal passages. Where the liquid carrier is
used, the formulation may be administered as a nasal spray or drops
and may include oil or aqueous solutions of the active
ingredients.
[0347] In addition to the formulations described above, a
formulation can optionally include, or be co-administered with one
or more additional drugs. The formulation may also contain
preserving agents, solubilizing agents, chemical buffers,
surfactants, emulsifiers, colorants, odorants and sweeteners.
[0348] A "subject" is a mammal, preferably a human, but can also be
an animal in need of veterinary treatment, e.g., companion animals
(e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep,
pigs, horses, and the like) and laboratory animals (e.g., rats,
mice, guinea pigs, and the like).
[0349] As noted above, one embodiment of the present invention is
directed to treating subjects with an immunosensitive cancer.
"Treating a subject with an immunosensitive cancer" includes
achieving, partially or substantially, one or more of the following
results: arresting the growth or spread of a cancer, reducing the
extent of a cancer (e.g., reducing size of a tumor or reducing the
number of affected sites), inhibiting the growth rate of a cancer,
and ameliorating or improving a clinical symptom or indicator
associated with a cancer. "Treating a subject with an
immunosensitive cancer" also includes partially or totally
inhibiting, delaying or preventing the progression of cancer
including cancer metastasis; partially or totally inhibiting,
delaying or preventing the recurrence of cancer including cancer
metastasis (in a subject who has been treated for cancer); or
partially or totally preventing the onset or development of cancer
(chemoprevention). Partially or totally inhibiting, delaying or
preventing the recurrence of means inhibiting, delaying or
preventing the recurrence of the cancer, after the original tumor
has been removed, for example, by surgery. A subject who has been
"treated for an immunosensitive cancer", is a subject in which, for
example, the primary tumor has been, for example, removed
surgically or has gone into remission following treatment by, for
example, chemotherapy.
[0350] The term "effective amount" is the quantity of compound in
which a beneficial clinical outcome is achieved when the compound
is administered to a subject with a cancer. A "beneficial clinical
outcome" includes prevention, inhibition or a delay in the
recurrence of cancer, a reduction in tumor mass, a reduction in
metastasis, a reduction in the severity of the symptoms associated
with the cancer and/or an increase in the longevity of the subject
compared with the absence of the treatment. The precise amount of
immunotherapy, compound or other anti-cancer agent administered to
a subject will depend on the type and severity of the disease or
condition and on the characteristics of the subject, such as
general health, age, sex, body weight and tolerance to drugs. It
will also depend on the degree, severity and type of cancer. The
skilled artisan will be able to determine appropriate dosages
depending on these and other factors. Effective amounts of the
disclosed bis(thiohydrazide amides) typically range between about 1
mg/mm.sup.2 per day and about 10 grams/mm.sup.2 per day, and
preferably between 10 mg/mm.sup.2 per day and about 5
grams/mm.sup.2. When co-administered with an immunotherapy or
another anti-cancer agent, an "effective amount" of the
immunotherapy or anti-cancer agent will depend on the type of drug
used. Suitable dosages are known for approved anti-cancer agents
and approved immunotherapies and can be adjusted by the skilled
artisan according to the condition of the subject, the type of
cancer being treated and the amount of bis(thio-hydrazide amide)
disalt being used.
[0351] Examples of specific dosage regimens for the disclosed
compounds used in combination with taxanes are provided below. When
combined with an immunotherapy, it is understood that an effective
amount of the immunotherapy is also used
[0352] One dosage regimen includes the step of co-administering to
the subject over three to five weeks, a taxane in an amount of
between about 243 .mu.mol/m2 to 315 .mu.mol/m2 (e.g., equivalent to
paclitaxel in about 210-270 mg/m2); and a bis(thiohydrazide amide)
(e.g., as represented by Structural Formula I) in an amount between
about 1473 .mu.mol/m2 and about 1722 .mu.mol/m2 (e.g., Compound (1)
in about 590-690 mg/m2).
[0353] In another dosage regimen the taxane and the
bis(thio-hydrazide) amide can each be administered in three equal
weekly doses for three weeks of a four week period. In preferred
embodiments, the four week administration period can be repeated
until the cancer is in remission. The taxane can be any taxane
defined herein. In a specific embodiment, the taxane is paclitaxel
intravenously administered in a weekly dose of about 94 .mu.mol/m2
(80 mg/m2). Typically, the bis(thiohydrazide amide) can be
intravenously administered in a weekly dose of between about 500
.mu.mol/m2 and about 562 .mu.mol/m2, or more typically in a weekly
dose of about 532 .mu.mol/m2. (e.g., Compound (1) in about 590-690
mg/m2).
[0354] Another dosage regimen includes intravenously administering
to the subject in a four week period, three equal weekly doses of
paclitaxel in an amount of about 94 .mu.mol/m2; and compound (1) or
a pharmaceutically acceptable salt or solvate thereof in an amount
of about 532 .mu.mol/m2.
[0355] In another dosage regimen, the subject can be intravenously
administered between about 220 .mu.mol/m2 and about 1310 .mu.mol/m2
(e.g., Compound (1) in about 88-525 mg/m2) of the bis(thiohydrazide
amide) once every 3 weeks, generally between about 220 .mu.mol/m2
and about 1093 .mu.mol/m2 (e.g., Compound (1) in about 88-438
mg/m2) once every 3 weeks, typically between about 624 .mu.mol/m2
and about 1124 .mu.mol/m2 m2 (e.g., Compound (1) in about 250-450
mg/m2), more typically between about 811 .mu.mol/m2 and about 936
.mu.mol/m2 m2 (e.g., Compound (1) in about 325-375 mg/m2), or in
particular embodiments, about 874 .mu.mol/m2 ((e.g., Compound (1)
in about 350 mg/m2). In particular embodiments, the subject can be
intravenously administered between about 582 .mu.mol/m2 and about
664 .mu.mol/m2 (e.g., Compound (1) in about 233-266 mg/m2) of the
bis(thiohydrazide amide) once every 3 weeks. In certain
embodiments, the bis(thiohydrazide amide) is in an amount of about
664 .mu.mol/m2 (e.g., Compound (1) in about 266 mg/m2).
[0356] In another dosage regimen, the subject can be intravenously
administered between about 200 .mu.mol/m2 to about 263 .mu.mol/m2
of the taxane as paclitaxel once every 3 weeks (e.g., paclitaxel in
about 175-225 mg/m2). In some embodiments, the subject can be
intravenously administered between about 200 .mu.mol/m2 to about
234 .mu.mol/m2 of the taxane as paclitaxel once every 3 weeks
(e.g., paclitaxel in about 175-200 mg/m2). In certain embodiments,
the paclitaxel is administered in an amount of about 234 .mu.mol/m2
(200 mg/m2). In certain embodiments, the paclitaxel is administered
in an amount of about 205 .mu.mol/m2 (175 mg/m2).
[0357] In one embodiment, the taxane, e.g., paclitaxel, and the
bis(thiohydrazide amide), e.g., Compound (1), can be administered
together in a single pharmaceutical composition.
[0358] In one embodiment, the method of the present invention
includes treating a subject once every three weeks, independently
or together a taxane in an amount of about 205 .mu.mol/m2 (e.g.,
paclitaxel in about 175 mg/m2); and a bis(thiohydrazide amide)
represented by Structural Formula I or a pharmaceutically
acceptable salt or solvate thereof in an amount between about 220
.mu.mol/m2 and about 1310 .mu.mol/m2 (e.g., Compound (1) in about
88-525 mg/m2). Typically, the taxane is paclitaxel intravenously
administered in an amount of about 205 .mu.mol/m2. The
bis(thiohydrazide amide) can typically be intravenously
administered between about 220 .mu.mol/m2 and about 1093 .mu.mol/m2
(e.g., Compound (1) in about 88-438 mg/m2), more typically between
about 749 .mu.mol/m2 and about 999 .mu.mol/m2 (e.g., compound (1)
in about 300-400 mg/m2), in some embodiments between about 811
.mu.mol/m2 and about 936 .mu.mol/m2 (e.g., Compound (1) in about
325-375 mg/m2). In certain embodiments, the bis(thiohydrazide
amide) can be Compound (1) intravenously administered between about
874 .mu.mol/m2 (about 350 mg/m2).
[0359] In a particular embodiment, the methods of the present
invention involve intravenously administering to the subject in a
single dose per three week period: paclitaxel in an amount of about
205 .mu.mol/m2 (175 mg/m2); and Compound (1) or a pharmaceutically
acceptable salt or solvate thereof in an amount of about 874
.mu.mol/m2 (350 mg/m2).
[0360] Particular formulations, dosages and modes of administration
are as described in US Publication No. 20060135595 and
PCT/US2005/014531 filed 13 Apr. 2006, titled Combination Cancer
Therapy With Bis[Thiohydrazide] Amide Compounds the entire contents
of each of which are incorporated herein by reference).
[0361] The bis(thio-hydrazide amide) disclosed herein can be
prepared by the methods described in U.S. Publication Nos.
20060135595, 2003/0045518 and 2003/0119914, U.S. application Ser.
No. 11/432,307, filed 11 May 2006, titled Synthesis Of
Bis(Thio-Hydrazide Amide) Salts, U.S. Provisional Patent No.
60/708,977 filed 16 Aug. 2005, titled Bis(Thio-Hydrazide Amide)
Formulation and also according to methods described in U.S.
Publication No. 2004/0225016 A1, entitled TREATMENT FOR CANCERS.
The entire teachings of these applications are incorporated herein
by reference.
[0362] The present invention is illustrated by the following
examples, which are not intended to be limiting in any way.
EXEMPLIFICATION
Example 1
Weekly Treatment Regimen of Compound (1) and Paclitaxel Combined in
Stage IV Metastatic Melanoma Patients in Comparison with Paclitaxel
Alone, Based on Time to Progression
[0363] A total of 81 people with Stage IV melanoma were tested in a
randomized trial with ratios of 2:1, compound (1)+paclitaxel (53
people): paclitaxel alone (28 people). The dosages administered
were 213 mg/m.sup.2 compound (1), 80 mg/m.sup.2 paclitaxel, and the
dosage regimen was 3 weekly doses per each 4 week cycle. Patients
were treated until progression of the disease. Patients who
progressed on paclitaxel alone were given the option to crossover
to compound (1)+paclitaxel and were treated until progression. The
tumor assessments were performed at baseline, Cycle 2, and every
other Cycle thereafter.
[0364] The baseline grades of metastatic diseases of the patients
are shown below:
TABLE-US-00001 compound (1) + Paclitaxel Paclitaxel (n = 53) (n =
28) M1a - metastasis to distant skin and 7 (13%) 2 (7%)
subcutaneous tissue M1b - metastasis to lungs 18 (34%) 5 (18%) M1c
- metastasis to other distant 28 (53%) 21 (75%) organs, such as
liver and brain
[0365] Though the majority of the patients in the paclitaxel alone
treatment group were M1c, an analysis of the effect of M grade did
not show a statistically significant effect on the patient's
likelihood of progressing more quickly (p-value=0.5368). The actual
treatment the patient received did have a statistically significant
effect on the patient's likelihood of progressing more quickly
(p-value=0.0281).
[0366] The probability-value for the continuum of potential
outcomes was divided into four scenarios from best to worst:
[0367] i) Inverted or Equal results;
[0368] ii) 4783 better p>0.2;
[0369] iii) Favorable 0.05<p<0.2 to; and
[0370] iv) Favorable p<0.05.
[0371] Table 1 shows the Kaplier Meyer estimates of the Time to
Progression of the disease (Efficacy Sample):
TABLE-US-00002 TABLE 1 compound (1) + Paclitaxel Paclitaxel (n =
50) (n = 27) p-value* Time to Progression (days) 25.sup.th
percentile (95% 54.0 (49.0, 95.0) 49.0 (29.0, 52.0) 0.017
confidence interval (CI)) Median (95% CI) 134.0 (86.0, 217.0 56.0
(49.0, 105.0) 75.sup.th percentile 273.0 (168.0, 331.0) 106.0
(61.0, 218.0) (95% CI) The p-value is from a log-rank test
[0372] Based on the four scenarios above the study results are in
line with the best of the four possible scenarios.
[0373] Table 2 shows the best overall response per Response
Evaluation Criteria In Solid Tumors (RECIST) (Efficacy Sample)
TABLE-US-00003 TABLE 2 compound (1) + Paclitaxel Paclitaxel (n =
50) (n = 27) p-value* Best Overall Response Complete 1 (2.0%) 0
Response (CR) Partial 7 (14.0%) 1 (3.7%) Response (PR) Stable 25
(50.0%) 10 (37%) Disease (SD) Progressive 17 (34.0%) 16 (59.3%)
Disease (PD) Two-Sided Fisher's Exact Test CR + PR (95% CI) 16.0%
(7.2%, 29.1%) 3.7% (0.1%, 19.0%) 0.149
[0374] As can be seen from Table 2 compounds of the present
invention in combination with paclitaxel show a significant
improvement over paclitaxel alone. Specifically compounds of the
present invention in combination with paclitaxel showed one patent
with a complete response and over 50% of the patients had stable
disease compared with Paclitaxel alone which only showed 37% of the
patients with stable disease.
[0375] Tables 3 and 4 show the relative treatment results of
compound (1) in combination with Paclitaxel compared with
Paclitaxel alone and other currently used treatments for melanoma.
As can be seen from Tables 3 and 4 the number of days to
progression of the disease is greatly enhanced for compound (1) in
combination with Paclitaxel compared with Paclitaxel alone. In
addition the time to progression benefit is much better than any
single-agent therapy and much better than all but one combination
therapy.
[0376] The combination therapy, cisplatin vinblastine dacarbazine
IL-2 and IFN, which had a longer time to progression than compound
(1) in combination with Paclitaxel, however, has severe side
effects and requires patients to be hospitalized for administration
of the combination. Conversely, compound (1) in combination with
Paclitaxel only showed a mild increase in the side effects over
Paclitaxel alone. None of the side effect were sever enough to
cause any patients to discontinue treatment with compound (1) in
combination with Paclitaxel during the trial.
TABLE-US-00004 TABLE 3 Regimen CR PR OR TTP Survival Agent (%) (%)
(%) (days) (months) Natural disease 6-9 progression "Any Treatment"
5-10 Single-Agent Chemotherapy DTIC (dacarbazine) rare 10-20 no
<3 improve- ment Temozolomide 2.6 9.6% 13.5 58 7.7 (Temodar)
Paclitaxel (Taxol) 12, 17.8 Paclitaxel 0 3.7 3.7 57 N.D.
Fotemustine 15.2 55 7.3 Sorafenib 2.6 Anti-Estrogen Therapy
Tamoxifen 1 3.9 4.9
TABLE-US-00005 TABLE 4 Regimen CR PR OR TTP Survival Agent (%) (%)
(%) (days) (months) Natural disease 6-9 progression "Any Treatment"
5-10 Biologic Response Modifiers Interleukin-2 6 10 14.3, 16 8.7,
<12 (IL-2; Proleukin .RTM.) Interferon (IFN alfa-2b, 3-5 15 IFN)
Biochemotherapy INF in combination 24 MDX-010 + IL-2 5.6 16.7 22.2
MDX-010 + MDX-1379 3.6 8.9 12.5 Dacarbazide + Genasense 11.7 78 9.1
Dacarbazide + Cisplatin + 92 9 IFN Dacarbazide + Cisplatin + 119 9
IFN + IL-2 Paclitaxel+: compound (1) 2.0 14.0 16 134 N.D. Cisplatin
+ vinblastine + 6.6 149 11.9 dacarbazine + IL-2 + IFN Carmustine +
dacarbazine + 13 30 43 cisplatin + Nolvadex + IL-2 + IFN cisplatin
vinblastine dacarbazine IL-2 and IFN
cisplatin vinblastine dacarbazine IL-2 and IFN
Example 2
Compounds of the Invention Accumulate in the Kidneys
[0377] A study was designed to investigate the tissue distribution
of compounds (1) and (18) in SW female mice, N=2 per group (total 4
groups including vehicle control. Reagents were obtained from
Sigma, St Louis, Mo.; mice were obtained from Taconic Farms
(Germantown N.Y.). The vehicle employed was 10% DMSO, 18% Cremophor
RH40. The compounds were administered intravenously at a dose of 25
mg/kg. Blood was collected 30 mM after administration, and tissue
collection was performed immediately after blood collection. Plasma
samples were prepared by combining 50 .mu.L plasma+50 .mu.l, 1%
dithiothreitol (DTT)+150 .mu.L, CH.sub.3CN (0.1% HCOOH),
centrifuged at 10,000 rpm.times.5 min; 150 .mu.L supernatant+90
.mu.L H.sub.2O. Tissue samples were prepared by homogenizing a
weighed tissue sample in phosphor-buffered saline (PBS,
.times.1)+1% DTT (.times.1)+CH.sub.3CN (0.1% HCOOH) (.times.3)),
centrifuged at 10,000 rpm.times.5 min; 150 .mu.L supernatant+90
.mu.L, H.sub.2O. 100 .mu.L prepared samples were subjected to HPLC,
using 5-95% CH.sub.3CN (0.1% HCOOH) as the eluent. The running time
was 15 min. With this method, the retention times were 7.25 min for
compound (18) and 7.99 min for compound (1).
[0378] FIG. 1 is a bar graph showing the concentrations of compound
(1) and compound (18) in mouse plasma, brain, kidney, liver and
spleen measured 30 min after injection in a first experiment. FIG.
2 is a graph of the tissue distribution of compound (1) and
compound (18). Compound (1) was detected in the kidney at
concentrations of about 28 .mu.M which was about 211% of the
plasma. Compound (18) was detected in kidney at a concentration of
about 51 .mu.M, which was about 164% of the plasma concentration.
Therefore, both compounds effectively accumulate in the
kidneys.
Example 3
Direct Evidence that Compound 1 Induces the Generation of ROS in
Drug-Treated Cells
[0379] We performed a series of experiments to directly show that
Compound 1 induces the generation of ROS in drug-treated cells. In
these experiments, we monitored the production of ROS using the
cell permeable Carboxy-H.sub.2DCFDA probe. When this probe is
oxidized by ROS, it emits a green fluorescence that can be detected
using flow cytometry or fluorescent microscopy. Ramos cells were
treated with Compound 1 (0.5 .mu.M) for 24 hours or pre-treated
with 1.0 mM or 10 mM NAC for 1 hour prior to addition of Compound 1
was then washed gently once with warm HBSS/Ca/Mg (GIBCO.14025). 25
carboxy-H.sub.2DCFDA (Invitrogen. C400) working solution was added
to cover the cells, and the cells were incubated for 30 minutes at
37.degree. C., protected from light. The cells were gently washed
three times in warm HBSS/Ca/Mg. ROS levels, as determined by
fluorescence intensity, were determined by flow cytometry
(excitation at 495 nm, emission at 529 nm).
[0380] Treatment of Ramos cells for 24 hours with Compound 1
induced the generation of ROS in cells resulting in the oxidation
and activation of the Carboxy-H.sub.2DCFDA probe (FIG. 3).
Treatment of drug-treated cells with NAC almost completely blocked
the generation of ROS by Compound 1 (FIG. 4). Compound 1 induced
ROS in a time dependent manner and induction of ROS was observed as
early as 3 hours (FIG. 5). These data indicate that Compound 1
induces oxidative stress and ROS generation in drug-treated
cells.
Example 4
The Free-Radical Scavenger Tiron Also Blocks ROS Generation and
Hsp70 Induction by Compound 1
[0381] Tiron is a direct scavenger of ROS and is a potent inhibitor
of oxidative stress. Ramos cells were pre-treated with 500 mM Tiron
1 hour prior to addition of Compound 1 (0.5 .mu.M) for 24 hours,
then measurement of ROS levels was performed as in Example 3. The
addition of Tiron to Compound 1-treated cells blocked the ability
of Compound 1 to generate ROS (FIG. 6) and induce Hsp70 (FIG. 7).
These data demonstrate that multiple antioxidants with differing
mechanisms of action can block the activity of Compound 1.
Example 5
Compound 1 Enhances the Anti-Tumor Activity of Ionizing Radiation
Against Human Tumor Cells in a Mouse Xenograft Model
[0382] The human squamous non-small cell lung cancer cell line,
RERF-LC-AI (RCB0444; S. Kyoizumi, et al., Cancer Res. 45:3274-3281,
1985), was obtained from the Riken Cell Bank (Tsukubua, Ibaraki,
Japan). The cells were cultured in growth media prepared with
Iscove's Modified Dulbecco's Media, 10% fetal bovine serum (FBS),
1% 100.times. Penicillin-Streptomycin, 1% 100.times.L-glutamine, 1%
100.times. sodium pyruvate and 1% 100.times.MEM non-essential amino
acids. FBS was obtained from American Type Culture Collection
(Manassas, Va., USA) and all other reagents were obtained from
Invitrogen Corp. (Carlsbad, Calif., USA). Cells that had been
cryopreserved in liquid nitrogen were rapidly thawed at 37.degree.
C. and transferred to a tissue culture flask containing growth
media and then incubated at 37.degree. C. in a 5% CO.sub.2
incubator. To expand the cell line, growth media was replaced every
2-3 days until the flask became 90% confluent, typically in 5-7
days. Cultures were passaged by washing with 10 mL of room
temperature phosphate buffered saline (PBS) and then disassociating
cells by adding 5 mL 1.times. trypsin-EDTA and incubating at
37.degree. C. until the cells detached from the surface of the
flask. To inactivate the trypsin, 5 mL of growth media was added
and then the contents of the flask were centrifuged to pellet the
cells. The supernatant was aspirated and the cell pellet was
resuspended in 10 mL of growth media and the cell number determined
using a hemocytometer. Approximately 1-3.times.10.sup.6 cells per
flask were seeded into 175 cm.sup.2 flasks containing 50 mL of
growth media and incubated at 37.degree. C. in a 5% CO.sub.2
incubator. When the flasks reached 90% confluence, the above
passaging process was repeated until sufficient cells had been
obtained for implantation into mice.
[0383] Seven to eight week old, female homozygous
Crl:CD1-Foxn1.sup.nu/nu (Nude) mice were obtained from Charles
River Laboratories (Wilmington, Mass., USA). Animals were housed
4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,
acclimated for at least 1 week prior to use and fed normal
laboratory chow ad libitum. Studies were conducted on animals
between 9-10 weeks of age at implantation. To implant RERF-LC-AI
tumor cells into Nude mice, cell cultures were trypsinized as
above, washed in PBS and resuspended at a concentration of
5.times.10.sup.7 cells/mL in 50% growth media and 50% Matrigel
Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Mass.,
USA). Using a 27 gauge needle and 1 cc syringe, 0.1 mL of the cell
suspension was injected subcutaneously into the flanks of Nude
mice. Tumor volumes (V) were calculated by caliper measurement of
the width (W), length (L) and thickness (T) of tumors using the
following formula: V=0.5236.times.(L.times.W.times.T).
[0384] In vivo passaged RERF-LC-AI tumor cells (RERF-LC-AI.sup.IVP)
were isolated to improve the rate of tumor implantation relative to
the parental cell line in Nude mice. RERF-LC-AI tumors were
permitted to develop in vivo until they reached approximately 250
mm.sup.3 in volume, which required approximately 3 weeks following
implantation. Mice were euthanized via CO.sub.2 asphyxiation and
their exteriors sterilized with 70% ethanol in a laminar flow hood.
Using sterile technique, tumors were excised and diced in 50 mL PBS
using a scalpel blade. A single cell suspension was prepared using
a 55 mL Wheaton Safe-Grind tissue grinder (catalog #62400-358; VWR
International, West Chester, Pa., USA) by plunging the pestle up
and down 4-5 times without twisting. The suspension was strained
through a 70 .mu.M nylon cell strainer and then centrifuged to
pellet the cells. The resulting pellet was resuspended in 0.1 M
NH.sub.4Cl to lyse contaminating red blood cells and then
immediately centrifuged to pellet the cells. The cell pellet was
resuspended in growth media and seeded into 175 cm.sup.2 flasks
containing 50 mL of growth media at 1-3 tumors/flask or
approximately 1.times.10.sup.7 cells/flask. After overnight
incubation at 37.degree. C. in a 5% CO.sub.2 incubator,
non-adherent cells were removed by rinsing two times with PBS and
then the cultures were fed with fresh growth media. When the flasks
reached 90% confluence, the above passaging process was repeated
until sufficient cells had been obtained for implantation into mice
as described above.
[0385] RERF-LC-AI.sup.IVP tumors were then permitted to develop in
vivo until the majority reached 90-230 mm.sup.3 in tumor volume,
which required approximately 3 weeks following implantation.
Animals with oblong, very small or large tumors were discarded, and
only animals carrying tumors that displayed consistent growth rates
were selected for studies. Animals were randomized into treatment
groups so that the average tumor volumes of each group were similar
at the start of dosing. % T/C values, as a measure of efficacy,
were determined as follows: [0386] (i) If .DELTA.T>0: %
T/C=(.DELTA.T/.DELTA.C).times.100 [0387] (ii) If .DELTA.T<0: %
T/C=(.DELTA.T/T.sub.0).times.100 [0388] (iii) .DELTA.T=Change in
average tumor volume between start of dosing and the end of study.
[0389] (iv) .DELTA.C=Change in average tumor volume between start
of dosing and the end of study. [0390] (v) T.sub.0=Average tumor
volume at start of dosing.
[0391] To formulate Compound 1 in 10/18 DRD, stock solutions of the
test article were prepared by dissolving the appropriate amounts of
the compound in dimethyl sulfoxide (DMSO) by sonication in an
ultrasonic water bath. Stock solutions were prepared weekly, stored
at -20.degree. C. and diluted fresh each day for dosing. A solution
of 20% Cremophor RH40 (polyoxyl 40 hydrogenated castor oil; BASF
Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5% dextrose in
water (D5W; Abbott Laboratories, North Chicago, Ill., USA) was also
prepared by first heating 100% Cremophor RH40 at 50-60.degree. C.
until liquefied and clear, diluting 1:5 with 100% D5W, reheating
again until clear and then mixing well. This solution was stored at
room temperature for up to 3 months prior to use. To prepare 10/18
DRD formulations for daily dosing, DMSO stock solutions were
diluted 1:10 with 20% Cremophor RH40. The final 10/18 DRD
formulation for dosing contained 10% DMSO, 18% Cremophor RH40, 3.6%
dextrose, 68.4% water and the appropriate amount of test article.
Animals were intravenously (i.v.) injected with this formulation at
10 mL per kg body weight on five days each week (Monday, Tuesday,
Wednesday, Thursday, Friday) for a total of 15 doses.
[0392] Animals were irradiated using a calibrated .sup.137Cs
gamma-ray (0.662 MeV) Model 30 Mark I irradiator (J.L. Shepherd
& Associates, San Fernando, Calif., USA). Tumor-bearing animals
were anesthetized for approximately 4 minutes with inhaled
isoflurane (IsoFlo, Abbott Laboratories, North Chicago, Ill., USA)
delivered on a stream of oxygen at 0.8 L/min and 3% volume/volume
on a mobile anesthesia machine (VetEquip, Pleasanton, Calif., USA).
This resulted in sufficient anesthesia to immobilize the animals
for placement of each group of 4-5 animals into the irradiator, but
the effect typically wore off 1-2 minutes prior to completion of
irradiation for that group. Anesthetized animals were positioned in
the irradiator approximately 3 cm in front of the .sup.137Cs source
using a restraint device capable of holding 5 animals (J.L Shepherd
& Associates). Ionizing radiation was focused on the
subcutaneously implanted RERF-LC-AI.sup.IVP tumors through a 1 cm
wide collimator (J.L. Shepherd & Associates) placed in front of
the .sup.137Cs source. Animals were irradiated at 1.6 Gy (160 rad)
per minute. Dosimetry demonstrated an approximately 450:1 ratio of
focused radiation received by tumors relative to the head and
shoulder region of animals.
[0393] We investigated the ability of Compound 1 to enhance the in
vivo anti-tumor activity of ionizing radiation. As shown in FIG. 8,
treatment with neither 100 mg/kg Compound 1 dosed 5 times per week,
nor irradiation with 0.5 Gy ionizing radiation delivered 3 timers
per week, resulted in significant reductions in the growth rate of
RERF-LC-AI.sup.IVP cells in Nude mice, with % T/C values of 112 and
85, respectively. However, treatment with 0.5 Gy radiation
delivered 3 times per week, combined with 100 mg/kg Compound 1
dosed 5 times per week (Compound 1 was dosed 420 minutes after
irradiation), substantially decreased the growth rate of
RERF-LC-AI.sup.IVP cells in Nude mice, with a % T/C value of 47.
This effect was not associated with excessive toxicity, as each
treatment group had average bodyweight gains relative to the start
of the study of between +3.4% and +6.0% over the course of the
study.
[0394] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *