U.S. patent application number 13/059176 was filed with the patent office on 2011-11-03 for organoarsenic compounds and methods for the treatment of cancer.
Invention is credited to Philip B. Komarnitsky, Jonathan Lewis, Brian Eric Schwartz.
Application Number | 20110269697 13/059176 |
Document ID | / |
Family ID | 41707414 |
Filed Date | 2011-11-03 |
United States Patent
Application |
20110269697 |
Kind Code |
A1 |
Schwartz; Brian Eric ; et
al. |
November 3, 2011 |
ORGANOARSENIC COMPOUNDS AND METHODS FOR THE TREATMENT OF CANCER
Abstract
A method for treating a lymphoma selected from non-Hodgkin's and
Hodgkin's lymphoma comprising administering an organoarsenic
compound having a structure of the formula (I) wherein X is S or Se
and R.sub.1 and R.sub.2 are independently C.sub.1-30alkyl(R.sub.3,
R.sub.3', R.sub.4, R.sub.5, W and "n" are as defined in claim 1) in
particular where the compound is S-dimethylarsinoglutathione,
N-(2-S-dimethylarsinothiopropionyl)glycine,
2-amino-3-(dimethylarsino)thio-3-methylbutanoic acid,
S-dimethylarsino-thiosuccinic acid or
S-dipropylarsino-1-thioglycerol. ##STR00001##
Inventors: |
Schwartz; Brian Eric;
(Woodbridge, CT) ; Lewis; Jonathan; (Fairfield,
CT) ; Komarnitsky; Philip B.; (Chestnut Hill,
MA) |
Family ID: |
41707414 |
Appl. No.: |
13/059176 |
Filed: |
August 14, 2009 |
PCT Filed: |
August 14, 2009 |
PCT NO: |
PCT/US2009/053858 |
371 Date: |
April 29, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61189511 |
Aug 20, 2008 |
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Current U.S.
Class: |
514/19.3 ;
514/159; 514/188; 514/504; 530/331; 546/3; 556/70 |
Current CPC
Class: |
A61K 31/455 20130101;
A61P 35/00 20180101; A61K 31/285 20130101; A61P 35/02 20180101;
A61K 31/60 20130101 |
Class at
Publication: |
514/19.3 ;
514/504; 556/70; 514/159; 530/331; 514/188; 546/3 |
International
Class: |
A61K 38/06 20060101
A61K038/06; C07F 9/72 20060101 C07F009/72; A61P 35/00 20060101
A61P035/00; C07K 5/083 20060101 C07K005/083; A61K 31/555 20060101
A61K031/555; C07F 9/82 20060101 C07F009/82; A61K 31/285 20060101
A61K031/285; A61K 31/60 20060101 A61K031/60 |
Claims
1. A method for treating a lymphoma selected from non-Hodgkin's and
Hodgkin's lymphoma, comprising administering a compound having a
structure of formula (I) or a pharmaceutically acceptable salt
thereof ##STR00018## wherein X is S or Se; W is O, S, or (R)(R),
where each occurrence of R is independently H or a C.sub.1-2alkyl;
n is and integer from 0 to 20; R.sup.1 and R.sup.2 are
independently C.sub.1-30alkyl; R.sup.3 is --H, C.sub.1-10alkyl, or
C.sub.0-6alkyl-COOR.sup.6; R.sup.3' is H, amino, cyano, halogen,
aryl, aralkyl, heteroaryl, heteroaralkyl, carboxyl,
C.sub.1-10alkyl, C.sub.1-10alkenyl, or C.sub.1-10alkynyl; R.sup.4
is --OH, --H, --CH.sub.3, amino, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a glutamine substituent;
R.sup.5 is --OH, cyano, C.sub.1-10alkoxy, amino, O-aralkyl,
--OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a
glycine substituent; and R.sup.6 is H or C.sub.1-10alkyl.
2. A method of claim 1, wherein the compound is ##STR00019##
3. A method of claim 1 or 2, wherein the lymphoma is non-Hodgkin's
lymphoma.
4. A method of claim 1 or 2, wherein the lymphoma is Hodgkin's
lymphoma.
5. A method of claim 1 or 2, wherein the lymphoma is selected from
peripheral T-cell lymphoma (PTCL), diffuse large B-cell, marginal
zone lymphoma, and Hodgkin's nodular sclerosis.
6. A method of any one of claims 1 to 5, wherein the compound is
administered intravenously.
7. A method of any one of claims 1 to 6, wherein a dose of the
compound is 200-420 mg/m.sup.2.
8. A method of claim 7, wherein a dose of the compound is 300
mg/m.sup.2.
9. A method of any one of claims 1 to 8, wherein the compound is
administered daily for five days every four weeks.
10. A method of claim 9, wherein the compound is administered daily
for five consecutive days every four weeks.
11. Use of a compound having a structure of formula (I) or a
pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for treating a lymphoma selected from non-Hodgkin's and
Hodgkin's lymphoma ##STR00020## wherein X is S or Se; W is O, S, or
(R)(R), where each occurrence of R is independently H or a
C.sub.1-2alkyl; n is and integer from 0 to 20; R.sup.1 and R.sup.2
are independently C.sub.1-30alkyl; R.sup.3 is --H, C.sub.1-10alkyl,
or C.sub.0-6alkyl-COOR.sup.6; R.sup.3' is H, amino, cyano, halogen,
aryl, aralkyl, heteroaryl, heteroaralkyl, carboxyl,
C.sub.1-10alkyl, C.sub.1-10alkenyl, or C.sub.1-10alkynyl; R.sup.4
is --OH, --H, --CH.sub.3, amino, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a glutamine substituent;
R.sup.5 is --OH, cyano, C.sub.1-10alkoxy, amino, O-aralkyl,
--OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a
glycine substituent; and R.sup.6 is H or C.sub.1-10alkyl.
12. Use of claim 11, wherein the compound is ##STR00021##
13. Use of claim 11 or 12, wherein the lymphoma is non-Hodgkin's
lymphoma.
14. Use of claim 11 or 12, wherein the lymphoma is Hodgkin's
lymphoma.
15. Use of claim 11 or 12, wherein the lymphoma is selected from
peripheral T-cell lymphoma (PTCL), diffuse large B-cell, marginal
zone lymphoma, and Hodgkin's nodular sclerosis.
16. Use of any one of claims 11 to 15, wherein the compound is
administered intravenously.
17. Use of any one of claims 11 to 16, wherein a dose of the
compound is 200-420 mg/m.sup.2.
18. Use of claim 17, wherein a dose of the compound is 300
mg/m.sup.2.
19. Use of any one of claims 11 to 18, wherein the compound is
administered daily for five days every four weeks.
20. Use of claim 19, wherein the compound is administered daily for
five consecutive days every four weeks.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 61/189,511 filed Aug. 20, 2008, which is
incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
anti-cancer therapy. More particularly, it provides organic arsenic
compounds and methods for their use in treating cancers such as
leukemia and solid tumors.
BACKGROUND OF THE INVENTION
[0003] Despite progress in leukemia therapy, most adult patients
with leukemia still die from disease progression. Arsenic trioxide,
an inorganic compound, has been approved for the treatment of
patients with relapsed or refractory acute promyelocytic leukemia
(APL) and is being evaluated as therapy for other leukemia types.
Preliminary data from China and the recent experience in the U.S.,
however, suggest a role for arsenic trioxide in the other
hematologic cancers as well. Consequently, the activity of arsenic
trioxide as an anti-leukemic agent is currently being investigated
in many types of leukemia. Although the results look favorable in
terms of the response rate of some of the leukemia types that are
being investigated, systemic toxicity of arsenic trioxide is a
problem (Soignet et al., 1999; Wierniket al., 1999; Geissler et
al., 1999; Rousselot et al., 1999).
[0004] The only organic arsenical (OA) manufactured for human use,
melarsoprol, has been evaluated for antileukemic activity
(WO9924029, EP1002537). Unfortunately, this compound is excessively
toxic to patients with leukemia at concentrations used for the
treatment of trypanosomiasis. Therefore, there is a need to
identify arsenic derivatives that can be used for the treatment of
hematologic malignancies and cancer in general, that have similar
or greater activity and lower toxicity than arsenic trioxide.
SUMMARY OF THE INVENTION
[0005] The present invention provides organic arsenical compounds
with anti-cancer properties. In some embodiments, the present
invention provides compounds having a structure of formula (I) or a
pharmaceutically acceptable salt thereof
##STR00002## [0006] wherein [0007] X is S or Se; [0008] W is O, S,
or (R)(R), where each occurrence of R is independently H or
C.sub.1-2alkyl; [0009] n is an integer from 0 to 20; [0010] R.sup.1
and R.sup.2 are independently C.sub.1-30alkyl; [0011] R.sup.3 is
--H, C.sub.1-10alkyl, or C.sub.0-6alkyl-COOR.sup.6; [0012] R.sup.3'
is H, amino, cyano, halogen, aryl, aralkyl, heteroaryl,
heteroaralkyl, carboxyl, C.sub.1-10alkyl, C.sub.1-10alkenyl, or
C.sub.1-10alkynyl, preferably H; [0013] R.sup.4 is --OH, --H,
--CH.sub.3, amino, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a glutamine substituent;
[0014] R.sup.5 is --OH, cyano, C.sub.1-10alkoxy, amino, O-aralkyl,
--OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a
glycine substituent; and [0015] R.sup.6 is H or
C.sub.1-10alkyl.
[0016] In certain embodiments, the organic arsenicals are compounds
having a structure of formula (II)
##STR00003## [0017] wherein [0018] X is S or Se, preferably S;
[0019] W is O, S, or (R)(R), where each occurrence of R is
independently H or a C.sub.1-2alkyl, preferably O; [0020] Z is CH
or N, preferably N; [0021] R.sup.1 and R.sup.2 are independently
C.sub.1-10alkyl, preferably R.sup.1 and R.sup.2 are independently
selected from methyl, ethyl, propyl, and isopropyl; and [0022]
R.sup.5 is --OH, cyano, C.sub.1-10alkoxy, amino, O-aralkyl,
O-aralkyl, --OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl,
--OC(O)aryl, or a glycine substituent, preferably OH; [0023]
R.sup.6 is H or C.sub.1-10alkyl; [0024] R.sup.7 is selected from
halogen, --OH, C.sub.0-6alkyl-COOR.sup.6, C.sub.1-6alkyl,
C.sub.1-6alkoxy, amino, amido, cyano, and nitro; [0025] m is an
integer from 0 to 4, preferably 0.
[0026] Other objects, features, and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating preferred
embodiments of the invention, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will become apparent to those skilled in the
art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention provides a number of organic arsenic
compounds.
[0028] In certain embodiments, the organic arsenicals of the
present invention have a structure of formula (I) or a
pharmaceutically acceptable salt thereof.
##STR00004## [0029] wherein [0030] X is S or Se, preferably S;
[0031] W is O, S, or (R)(R), where each occurrence of R is
independently H or a C.sub.1-2alkyl, preferably O or (R)(R); [0032]
n is an integer from 0 to 20; [0033] R.sup.1 and R.sup.2 are
independently C.sub.1-30alkyl; [0034] R.sup.3 is --H,
C.sub.1-10alkyl, or C.sub.0-6alkyl-COOR.sup.6; [0035] R.sup.3' is
H, amino, cyano, halogen, aryl, aralkyl, heteroaryl, heteroaralkyl,
carboxyl, C.sub.1-10alkyl, C.sub.1-10alkenyl, or C.sub.1-10alkynyl,
preferably H; [0036] R.sup.4 is --OH, --H, --CH.sub.3, amino,
--OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a
glutamine substituent; [0037] R.sup.5 is --OH, cyano,
C.sub.1-10alkoxy, amino, O-aralkyl, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a glycine substituent; and
[0038] R.sup.6 is H or C.sub.1-10alkyl, preferably H.
[0039] In certain embodiments, W is (R)(R) and each occurrence of R
is independently H or a C.sub.1-2alkyl. In certain such
embodiments, each occurrence of R is H.
[0040] In certain embodiments, n is 0 or 1, preferably 1. In
certain embodiments, n is an integer from 2 to 20, preferably from
5 to 20 or 9 to 14.
[0041] In certain embodiments, R.sup.1 and R.sup.2 are each
independently C.sub.11-30alkyl, preferably C.sub.12-28alkyl,
C.sub.13-25alkyl, C.sub.14-22alkyl, or even C.sub.15-20alkyl.
[0042] In certain embodiments, R.sup.1 and R.sup.2 are
C.sub.1-10alkyl, preferably R.sup.1 and R.sup.2 are independently
selected from methyl, ethyl, propyl, and isopropyl
[0043] In certain embodiments, R.sup.3 is --H or
C.sub.0-6alkyl-COOR.sup.6. In certain such embodiments, R.sup.3 is
selected from --COOR.sup.6, --CH.sub.2COOR.sup.6,
--CH.sub.2CH.sub.2COOR.sup.6, --CH(CH.sub.3)COOR.sup.6,
--CH(CH.sub.2CH.sub.3)COOR.sup.6, or
--CH.sub.2CH.sub.2CH.sub.2COOR.sup.6, wherein R.sup.6 is
C.sub.1-10alkyl.
[0044] In certain embodiments, R.sup.3 is C.sub.1-10alkyl. In
certain preferred such embodiments, R.sup.3 is selected from
methyl, ethyl, propyl, and isopropyl, preferably methyl.
[0045] In certain embodiments, R.sup.3' is selected from amino,
cyano, halogen, aryl, aralkyl, heteroaryl, heteroaralkyl, carboxyl,
C.sub.1-10alkyl, C.sub.1-10alkenyl, and C.sub.1-10alkynyl. In
preferred such embodiments, R.sup.3' is selected from aryl,
aralkyl, heteroaryl, heteroaralkyl, carboxyl, C.sub.1-10alkenyl,
and C.sub.1-10alkynyl
[0046] In certain embodiments, R.sup.4 is selected from --OH, --H,
--CH.sub.3, --OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl, and
--OC(O)aryl. In certain such embodiments, R.sup.4 is selected from
--OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl, and
--OC(O)aryl.
[0047] In certain embodiments, R.sup.4 is amino. In certain such
embodiments, R.sup.4 is NH.sub.2.
[0048] In certain embodiments, R.sup.4 is a glutamine
substituent.
[0049] In certain embodiments, R.sup.5 is selected from cyano,
C.sub.1-10alkoxy, amino, O-aralkyl, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, and --OC(O)aryl.
[0050] In certain embodiments, X is S, W is (R)(R), wherein each
occurrence of R is H, n is 1, R.sup.1 and R.sup.2 are independently
selected from methyl, ethyl, propyl, and isopropyl, R.sup.3 and
R.sup.3' are H, R.sup.4 is selected from OH,
--OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl, and --OC(O)aryl
and, and R.sup.5 is selected from OH, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, and --OC(O)aryl. In certain such
embodiments, R.sup.1 and R.sup.2 are the same and are together
selected from methyl, ethyl, propyl, and isopropyl.
[0051] In certain embodiments, X is S, W is O, n is 1, R.sup.1 and
R.sup.2 are both methyl, R.sup.3 is selected from H and COOR.sup.6,
R.sup.3' is H, and R.sup.4 is selected from H and a glutamine
substituent, and R.sup.5 is selected from OH and a glycine
substituent. In certain such embodiments, R.sup.3 is COOR.sup.6,
R.sup.4 is H, R.sup.5 is OH, and R.sup.6 is H.
[0052] In certain embodiments, compounds of formula (I) are
selected from
##STR00005## ##STR00006##
[0053] or a pharmaceutically acceptable salt thereof.
[0054] In certain embodiments, compounds of formula (I) are
selected from
##STR00007##
[0055] or a pharmaceutically acceptable salt thereof.
[0056] In certain embodiments, compounds of formula (I) are
selected from
##STR00008##
[0057] or a pharmaceutically acceptable salt thereof.
[0058] In certain embodiments, compounds of formula (I) are
selected from
##STR00009##
[0059] In certain embodiments, a compound of formula (I) is
##STR00010##
[0060] In certain embodiments, a compound of formula (I) is
##STR00011##
[0061] or a pharmaceutically acceptable salt thereof.
[0062] If a chiral center is present, all isomeric forms are within
the scope of the invention. Regarding the stereochemistry, the
Cahn-Ingold-Prelog rules for determining absolute stereochemistry
are followed. These rules are described, for example, in Organic
Chemistry, Fox and Whitesell; Jones and Bartlett Publishers,
Boston, Mass. (1994); Section 5-6, pp 177-178, which section is
hereby incorporated by reference.
[0063] In certain embodiments, the organic arsenicals are compounds
having a structure of formula (II)
##STR00012## [0064] wherein [0065] X is S or Se, preferably S;
[0066] W is O, S, or (R)(R), where each occurrence of R is
independently H or a C.sub.1-2alkyl, preferably O; [0067] Z is CH
or N; [0068] R.sup.1 and R.sup.2 are independently C.sub.1-10alkyl,
preferably R.sup.1 and R.sup.2 are independently selected from
methyl, ethyl, propyl, and isopropyl; and [0069] R.sup.5 is --OH,
cyano, C.sub.1-10alkoxy, amino, O-aralkyl, O-aralkyl,
--OC(O)C.sub.1-10aralkyl, --OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a
glycine substituent, preferably OH; [0070] R.sup.6 is H or
C.sub.1-10alkyl; [0071] R.sup.7 is selected from halogen, --OH,
C.sub.0-6alkyl-COOR.sup.6, C.sub.1-6alkyl, C.sub.1-6alkoxy, amino,
amido, cyano, and nitro; [0072] m is an integer from 0 to 4,
preferably 0.
[0073] In certain embodiments, W is (R)(R) and each occurrence of R
is independently H or a C.sub.1-2alkyl. In certain such
embodiments, each occurrence of R is H.
[0074] In certain embodiments, R.sup.5 is selected from cyano,
C.sub.1-10alkoxy, amino, O-aralkyl, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, and --OC(O)aryl.
[0075] In certain embodiments X is S, W is O, R.sup.1 and R.sup.2
are independently selected from methyl, ethyl, propyl, and
isopropyl, and R.sup.5 is OH. In certain such embodiments, R.sup.1
and R.sup.2 are the same and are together selected from methyl,
ethyl, propyl, and isopropyl. In certain such embodiments, R.sup.1
and R.sup.2 are both methyl.
[0076] In certain embodiments, Z is N.
[0077] In certain embodiments, Z is CH.
[0078] In certain embodiments, a compound of formula (II) is
selected from
##STR00013##
[0079] In certain embodiments, a compound of formula (II) is
##STR00014##
[0080] In other embodiments, the organic arsenicals are compounds
having a structure of formula (III)
##STR00015## [0081] wherein [0082] X is S or Se, preferably S;
[0083] W is O, S, or (R)(R), where each occurrence of R is
independently H or a C.sub.1-2alkyl, preferably O; [0084] R.sup.1
and R.sup.2 are independently C.sub.1-10alkyl, preferably R.sup.1
and R.sup.2 are independently selected from methyl, ethyl, propyl,
and isopropyl; and [0085] R.sup.5 is --OH, cyano, C.sub.1-10alkoxy,
amino, O-aralkyl, O-aralkyl, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, --OC(O)aryl, or a glycine substituent,
preferably OH; [0086] R.sup.6 is H or C.sub.1-10alkyl; [0087]
R.sup.7 is selected from halogen, --OH, C.sub.0-6alkyl-COOR.sup.6,
C.sub.1-6alkyl, C.sub.1-6alkoxy, amino, amido, cyano, and nitro;
[0088] m is an integer from 0 to 4, preferably 0.
[0089] In certain embodiments, W is (R)(R) and each occurrence of R
is independently H or a C.sub.1-2alkyl. In certain such
embodiments, each occurrence of R is H.
[0090] In certain embodiments, R.sup.5 is selected from cyano,
C.sub.1-10alkoxy, amino, O-aralkyl, --OC(O)C.sub.1-10aralkyl,
--OC(O)C.sub.1-10alkyl, and --OC(O)aryl.
[0091] In certain embodiments X is S, W is O, R.sup.1 and R.sup.2
are independently selected from methyl, ethyl, propyl, and
isopropyl, and R.sup.5 is OH. In certain such embodiments, R.sup.1
and R.sup.2 are the same and are together selected from methyl,
ethyl, propyl, and isopropyl. In certain such embodiments, R.sup.1
and R.sup.2 are both methyl.
[0092] In certain preferred embodiments, a compound of formula (II)
has the following structure
##STR00016##
[0093] The invention further provides pharmaceutical compositions
comprising formula (I), formula (II), or formula (III), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable diluent or carrier. In certain embodiments, the
pharmaceutical composition is an aqueous solution that has a pH
greater than about 5, preferably in the range from about 5 to about
8, more preferably in the range from about 5 to about 7.
[0094] Another aspect of the invention provides a method for the
treatment of cancer comprising administering a therapeutically
effective amount of a compound of formula (I), formula (II), or
formula (III).
[0095] The invention also relates to the use of a compound of
formula (I), formula (II), or formula (III), or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for the
treatment of cancer.
[0096] In certain embodiments, the cancer is selected from a solid
tumor, such as brain, lung, liver, spleen, kidney, lymph node,
small intestine, pancreas, blood cells, bone, colon, stomach,
breast, endometrium, prostate, testicle, ovary, central nervous
system, skin, head and neck, esophagus, or bone marrow, or a
hematological cancer, such as leukemia, acute promyelocytic
leukemia, lymphoma, multiple myeloma, myelodysplasia,
myeloproliferative disease, or refractory leukemia. In certain such
embodiments, the cancer is a leukemia selected from acute and
chronic leukemia.
[0097] In certain embodiments, the cancer is a lymphoma selected
from non-Hodgkin's and Hodgkin's lymphoma. In certain embodiments,
the non-Hodgkin's lymphoma is selected from peripheral T-cell
lymphoma (PTCL), diffuse large B-cell lymphoma, and marginal zone
lymphoma. In certain embodiments, the Hodgkin's lymphoma is
Hodgkin's nodular sclerosis.
[0098] Thus, in another aspect, the invention comprises a method of
treating a patient with cancer comprising administering to the
patient a composition comprising a compound of formula I, formula
II, or formula III, or pharmaceutical composition as described
above. The therapeutically effective amount of a compound may be
0.1-1000 mg/kg, 1-500 mg/kg, or 10-100 mg/kg. In particular
embodiments, the method may comprise administering the composition
daily. It is further contemplated that treatment methods may
involve multiple administrations. The method may comprise
administering the compound daily such as by injection. Alternative
routes and methods of administration described in the specification
may also be used and the mode of administration will mainly depend
on the type and location of the cancer. In certain embodiments, the
method further comprises administering one or more additional
agents to the patient. The additional agent may be
all-trans-retinoic acid, 9-cis retinoic acid, Am-80, or ascorbic
acid. The use of other adjunct cancer therapies, such as
chemotherapy, radiotherapy, gene therapy, hormone therapy, and
other cancer therapies known in the art are also contemplated in
conjunction with the methods of the present invention.
[0099] Various methods of administration are contemplated,
including regional, systemic, direct administration and by
perfusion. Such methods include administration by injection, oral
routes, intravenous, intraarterial, intratumoral, administration to
tumoral vasculature, intraperitoneal, intratracheal, intramuscular,
endoscopical, intralesional, percutaneous, subcutaneous, topical,
nasal, buccal, mucosal, anogenital, rectal and the like.
DEFINITIONS
[0100] The term "C.sub.x-yalkyl" refers to substituted or
unsubstituted saturated hydrocarbon groups, including
straight-chain alkyl and branched-chain alkyl groups that contain
from x to y carbons in the chain, including haloalkyl groups such
as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. C.sub.0alkyl
indicates a hydrogen where the group is in a terminal position, a
bond if internal. The terms "C.sub.2-yalkenyl" and
"C.sub.2-yalkynyl" refer to substituted or unsubstituted
unsaturated aliphatic groups analogous in length and possible
substitution to the alkyls described above, but that contain at
least one double or triple bond respectively.
[0101] The term "C.sub.1-6alkoxy" refers to an C.sub.1-6alkyl group
having an oxygen attached thereto. Representative alkoxy groups
include methoxy, ethoxy, propoxy, tert-butoxy and the like. An
"ether" is two hydrocarbons covalently linked by an oxygen.
Accordingly, the substituent of an alkyl that renders that alkyl an
ether is or resembles an alkoxy.
[0102] The term "C.sub.1-6aralkyl", as used herein, refers to a
C.sub.1-6alkyl group substituted with an aryl group.
[0103] The term "aryl" as used herein includes 5-, 6-, and
7-membered substituted or unsubstituted single-ring aromatic groups
in which each atom of the ring is carbon. The term "aryl" also
includes polycyclic ring systems having two or more cyclic rings in
which two or more carbons are common to two adjoining rings wherein
at least one of the rings is aromatic, e.g., the other cyclic rings
can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,
heteroaryls, and/or heterocyclyls. Aryl groups include benzene,
naphthalene, phenanthrene, phenol, aniline, and the like.
[0104] The phrase "pharmaceutically acceptable" is employed herein
to refer to those ligands, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0105] The term "preventing" is art-recognized, and when used in
relation to a condition, such as a local recurrence (e.g., pain), a
disease such as cancer, a syndrome complex such as heart failure or
any other medical condition, is well understood in the art, and
includes administration of a composition which reduces the
frequency of, or delays the onset of, symptoms of a medical
condition in a subject relative to a subject which does not receive
the composition. Thus, prevention of cancer includes, for example,
reducing the number of detectable cancerous growths in a population
of patients receiving a prophylactic treatment relative to an
untreated control population, and/or delaying the appearance of
detectable cancerous growths in a treated population versus an
untreated control population, e.g., by a statistically and/or
clinically significant amount. Prevention of an infection includes,
for example, reducing the number of diagnoses of the infection in a
treated population versus an untreated control population, and/or
delaying the onset of symptoms of the infection in a treated
population versus an untreated control population. Prevention of
pain includes, for example, reducing the magnitude of, or
alternatively delaying, pain sensations experienced by subjects in
a treated population versus an untreated control population.
[0106] The term "prophylactic or therapeutic" treatment is
art-recognized and includes administration to the host of one or
more of the subject compositions. If it is administered prior to
clinical manifestation of the unwanted condition (e.g., disease or
other unwanted state of the host animal) then the treatment is
prophylactic, (i.e., it protects the host against developing the
unwanted condition), whereas if it is administered after
manifestation of the unwanted condition, the treatment is
therapeutic, (i.e., it is intended to diminish, ameliorate, or
stabilize the existing unwanted condition or side effects
thereof).
[0107] The term "substituted" refers to moieties having
substituents replacing a hydrogen on one or more carbons of the
backbone. It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc. As used
herein, the term "substituted" is contemplated to include all
permissible substituents of organic compounds. In a broad aspect,
the permissible substituents include acyclic and cyclic, branched
and unbranched, carbocyclic and heterocyclic, aromatic and
non-aromatic substituents of organic compounds. The permissible
substituents can be one or more and the same or different for
appropriate organic compounds. For purposes of this invention, the
heteroatoms such as nitrogen may have hydrogen substituents and/or
any permissible substituents of organic compounds described herein
which satisfy the valences of the heteroatoms. Substituents can
include, for example, a halogen, a hydroxyl, a carbonyl (such as a
carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl
(such as a thioester, a thioacetate, or a thioformate), an alkoxyl,
a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino,
an amido, an amidine, an imine, a cyano, a nitro, an azido, a
sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a
sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic
or heteroaromatic moiety. It will be understood by those skilled in
the art that the moieties substituted on the hydrocarbon chain can
themselves be substituted, if appropriate.
[0108] A "therapeutically effective amount" of a compound with
respect to the subject method of treatment refers to an amount of
the compound(s) in a preparation which, when administered as part
of a desired dosage regimen (to a mammal, preferably a human)
alleviates a symptom, ameliorates a condition, or slows the onset
of disease conditions according to clinically acceptable standards
for the disorder or condition to be treated or the cosmetic
purpose, e.g., at a reasonable benefit/risk ratio applicable to any
medical treatment.
[0109] As used herein, the term "regimen" is a predetermined
schedule of one or more therapeutic agents for the treatment of a
cancer. Accordingly, when a therapeutic agent is administered
"alone," the regimen does not include the use of another
therapeutic agent for the treatment of cancer.
[0110] In certain embodiments, the compound is administered daily
for five days every four weeks. In certain embodiments, the
compound is administered once daily for five days every four weeks,
preferably for five consecutive days. In certain alternative
embodiments, the compound is administered two days a week for three
weeks, followed by one week off. In certain such embodiments, the
compound is administered for two consecutive days or two
non-consecutive days (e.g., with one, two, three, or even four days
in between doses) a week for three weeks, followed by one week off.
In certain embodiments, these protocols can be repeated
indefinitely.
[0111] In certain embodiments, such dosing is by intravenous
administration. In certain alternative embodiments, such dosing is
by oral administration. In certain such embodiments, the compound
is administered intravenously at a dose of about 200-420 mg/m.sup.2
or about 250 to 350 m/m.sup.2. In certain embodiments, the compound
is administered at a dose of about 200, about 250, about 300, about
350, about 400 or even about 420 mg/m.sup.2. In certain
embodiments, the compound is administered orally at a total daily
dose of 300 to about 700 mg or about 400 to about 600 mg. In
certain embodiments, the compound is administered at a total daily
dose of 300, about 400, about 500, about 600, or even about 700
mg.
[0112] As used herein, the term "treating" or "treatment" includes
reversing, reducing, or arresting the symptoms, clinical signs, and
underlying pathology of a condition in manner to improve or
stabilize a subject's condition.
[0113] Toxicity of Inorganic vs. Organic Arsenicals
[0114] The use of arsenic trioxide is limited by its toxicity. OA,
on the other hand, are much less toxic, to the extent that the
methylation of inorganic arsenic in vivo into OA has been
considered to be a detoxification reaction. The OA
monomethylarsinic acid and dimethylarsinic acid are the primary
metabolites of inorganic arsenic (Hughes et al., 1998). Inorganic
arsenicals, including arsenic trioxide, have varied effects on many
organ systems, including cardiovascular system, gastrointestinal
tract, kidneys, skin, nervous system, and blood. Inorganic
arsenicals are particularly toxic to the liver, causing
infiltration, central necrosis, and cirrhosis (IARC, 1980: ACGIH,
1991; Beliles et al., 1994; Goyer et al., 1996). There is now
sufficient evidence that inorganic arsenic compounds are skin and
lung carcinogens in humans (Goyer et al., 1996).
[0115] The toxicity of a given arsenical is related to the rate of
its clearance from the body and to the extent of its tissue
accumulation (Beliles et al., 1994). In general, toxicity increases
in the following sequence: organic arsenicals
<As.sup.5+<As.sup.3+ (including arsenic trioxide)<arsine.
Unlike inorganic arsenicals, no deaths or serious cases of toxicity
due to OA have been reported in the literature. Consequently, in
mammals the methylation of inorganic arsenic has been considered a
detoxification mechanism because of the lower toxicity of
methylated OA, and their fast excretion and low retention (Beliles
et al., 1994; Goyer et al., 1996). A good example is that of
dimethylarsinic acid, an organic compound, the predominant urinary
metabolite excreted by most mammals after exposure to inorganic
arsenic, including arsenic trioxide. In in vivo toxicity studies in
mice, after intraperitoneal administration of arsenic trioxide, the
LD.sub.50 (a dose at which 50% of animals die due to acute
toxicity) was 10 mg/kg, (Investigator's Brochure, 1998), while
after administration of dimethylarsinic acid, the LD.sub.50 was 500
mg/kg (MSDS, 1998).
[0116] Cancer Treatment
[0117] The organic arsenicals of the current invention may be used
to treat a variety of cancers, including all solid tumors and all
hematological cancers, including leukemia, lymphoma, multiple
myeloma, myelodysplasia, or myeloproliferative disorders. The
organic arsenical can also be used to treat hematological cancers
that have become refractory to other forms of treatment.
[0118] In certain embodiments, the cancer is a lymphoma selected
from non-Hodgkin's and Hodgkin's lymphoma. In certain embodiments,
the non-Hodgkin's lymphoma is selected from peripheral T-cell
lymphoma (PTCL), diffuse large B-cell lymphoma, and marginal zone
lymphoma. In certain embodiments, the Hodgkin's lymphoma is
Hodgkin's nodular sclerosis.
[0119] Lymphoma is a type of blood cancer that occurs when
lymphocytes--white blood cells that help protect the body from
infection and disease--begin behaving abnormally. Abnormal
lymphocytes may divide faster than normal cells or they may live
longer than they are supposed to. Lymphoma may develop in many
parts of the body, including the lymph nodes, spleen, bone marrow,
blood, or other organs. There are two main types of lymphomas:
Hodgkin lymphoma and non-Hodgkin lymphoma (NHL).
[0120] Peripheral T-cell lymphomas are tumors composed of mature
T-cells (not B-cells). Peripheral T-cell lymphomas such as
angioimmunoblastic T-cell lymphoma or anaplastic large cell
lymphoma can arise in lymph nodes, while others like subcutaneous
panniculitis-like T-cell lymphoma, nasal NK/T-cell lymphoma, or
intestinal T-cell lymphoma can arise in extranodal sites.
[0121] Large cell lymphomas are the most common type of lymphoma.
These cancers may arise in lymph nodes or in extranodal sites,
including the gastrointestinal tract, testes, thyroid, skin,
breast, central nervous system, or bone and may be localized or
generalized (spread throughout the body).
[0122] Marginal zone tumors are indolent B-cell lymphomas and may
occur either outside lymph nodes (extranodal) or within lymph nodes
(nodal). They are divided into two categories depending on the
location of the lymphoma. Mucosa-associated lymphoid tissue
lymphomas (also called MALT or MALTomas) are forms of marginal zone
lymphomas that affect places outside the lymph nodes (such as the
gastrointestinal tract, eyes, thyroid, salivary glands, lungs, or
skin) Nodal marginal zone B-cell lymphomas are uncommon and are
sometimes called monocytoid B-cell lymphomas.
[0123] In Hodgkin's nodular sclerosis, the involved lymph nodes
contain areas composed of Reed-Sternberg cells mixed with normal
white blood cells. The lymph nodes often contain prominent scar
tissue, hence the name nodular sclerosis (scarring). This subtype
is the most common, making up 60% to 75% of all cases of Hodgkin's
lymphoma.
Pharmaceutical Compositions
[0124] The preparation of a pharmaceutical composition that
contains at least one organic arsenical or additional active
ingredient will be known to those of skill in the art in light of
the present disclosure, as exemplified by Remington's
Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990,
incorporated herein by reference. Moreover, for animal (e.g.,
human) administration, it will be understood that preparations
should meet sterility, pyrogenicity, general safety and purity
standards as required by FDA Office of Biological Standards.
[0125] As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives (e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drugs, drug stabilizers, gels,
binders, excipients, disintegration agents, lubricants, sweetening
agents, flavoring agents, dyes, such like materials and
combinations thereof, as would be known to one of ordinary skill in
the art (see, for example, Remington's Pharmaceutical Sciences,
18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated
herein by reference). Except insofar as any conventional carrier is
incompatible with the active ingredient, its use in the therapeutic
or pharmaceutical compositions is contemplated.
[0126] The organic arsenical may be combined with different types
of carriers depending on whether it is to be administered in solid,
liquid or aerosol form, and whether it need to be sterile for such
routes of administration as injection. The present invention can be
administered intravenously, intradermally, intraarterially,
intraperitoneally, intralesionally, intracranially,
intraarticularly, intraprostaticaly, intrapleurally,
intratracheally, intranasally, intravitreally, intravaginally,
intrarectally, topically, intratumorally, intramuscularly,
intraperitoneally, subcutaneously, subconjunctival,
intravesicularlly, mucosally, intrapericardially, intraumbilically,
intraocularally, orally, topically, locally, injection, infusion,
continuous infusion, localized perfusion bathing target cells
directly, via a catheter, via a lavage, in lipid compositions
(e.g., liposomes), or by other method or any combination of the
forgoing as would be known to one of ordinary skill in the art
(see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
Mack Printing Company, 1990, incorporated herein by reference).
[0127] The actual dosage amount of a composition of the present
invention administered to a patient can be determined by physical
and physiological factors such as body weight, severity of
condition, the type of disease being treated, previous or
concurrent therapeutic interventions, idiopathy of the patient and
on the route of administration. The practitioner responsible for
administration will, in any event, determine the concentration of
active ingredient(s) in a composition and appropriate dose(s) for
the individual subject.
[0128] In certain embodiments, pharmaceutical compositions may
comprise, for example, at least about 0.1% of an organic arsenical
compound. In other embodiments, the an active compound may comprise
between about 2% to about 75% of the weight of the unit, or between
about 25% to about 60%, for example, and any range derivable
therein. In other non-limiting examples, a dose may also comprise
from about 0.1 mg/kg/body weight, 0.5 mg/kg/body weight, 1
mg/kg/body weight, about 5 mg/kg/body weight, about 10 mg/kg/body
weight, about 20 mg/kg/body weight, about 30 mg/kg/body weight,
about 40 mg/kg/body weight, about 50 mg/kg/body weight, about 75
mg/kg/body weight, about 100 mg/kg/body weight, about 200
mg/kg/body weight, about 350 mg/kg/body weight, about 500
mg/kg/body weight, about 750 mg/kg/body weight, to about 1000
mg/kg/body weight or more per administration, and any range
derivable therein. In non-limiting examples of a derivable range
from the numbers listed herein, a range of about 10 mg/kg/body
weight to about 100 mg/kg/body weight, etc., can be administered,
based on the numbers described above.
[0129] In any case, the composition may comprise various
antioxidants to retard oxidation of one or more component.
Additionally, the prevention of the action of microorganisms can be
brought about by preservatives such as various antibacterial and
antifungal agents, including, but not limited to parabens (e.g.,
methylparabens, propylparabens), chlorobutanol, phenol, sorbic
acid, thimerosal or combinations thereof.
[0130] The organic arsenical may be formulated into a composition
in a free base, neutral or salt form. Pharmaceutically acceptable
salts include the salts formed with the free carboxyl groups
derived from inorganic bases such as for example, sodium,
potassium, ammonium, calcium or ferric hydroxides; or such organic
bases as isopropylamine, trimethylamine, histidine or procaine.
[0131] In embodiments where the composition is in a liquid form, a
carrier can be a solvent or dispersion medium comprising, but not
limited to, water, ethanol, polyol (e.g., glycerol, propylene
glycol, liquid polyethylene glycol, etc.), lipids (e.g.,
triglycerides, vegetable oils, liposomes) and combinations thereof.
The proper fluidity can be maintained, for example, by the use of a
coating, such as lecithin; by the maintenance of the required
particle size by dispersion in carriers such as, for example liquid
polyol or lipids; by the use of surfactants such as, for example
hydroxypropylcellulose; or combinations thereof such methods. In
many cases, it will be preferable to include isotonic agents, such
as, for example, sugars, sodium chloride or combinations
thereof.
[0132] Sterile injectable solutions are prepared by incorporating
the active compounds in the required amount of the appropriate
solvent with various of the other ingredients enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and/or the other ingredients. In the case of
sterile powders for the preparation of sterile injectable
solutions, suspensions or emulsion, the preferred methods of
preparation are vacuum-drying or freeze-drying techniques which
yield a powder of the active ingredient plus any additional desired
ingredient from a previously sterile-filtered liquid medium
thereof. The liquid medium should be suitably buffered if necessary
and the liquid diluent first rendered isotonic prior to injection
with sufficient saline or glucose. The preparation of highly
concentrated compositions for direct injection is also
contemplated, where the use of DMSO as solvent is envisioned to
result in extremely rapid penetration, delivering high
concentrations of the active agents to a small area.
[0133] The composition must be stable under the conditions of
manufacture and storage, and preserved against the contaminating
action of microorganisms, such as bacteria and fungi. Thus,
preferred compositions have a pH greater than about 5, preferably
from about 5 to about 8, more preferably from about 5 to about 7.
It will be appreciated that endotoxin contamination should be kept
minimally at a safe level, for example, less that 0.5 ng/mg
protein.
[0134] In particular embodiments, prolonged absorption of an
injectable composition can be brought about by the use in the
compositions of agents delaying absorption, such as, for example,
aluminum monostearate, gelatin or combinations thereof.
[0135] Combination Therapy
[0136] It is an aspect of this invention that the organic arsenical
can be used in combination with another agent or therapy method,
preferably another cancer treatment. The organic arsenical may
precede or follow the other agent treatment by intervals ranging
from minutes to weeks. In embodiments where the other agent and
expression construct are applied separately to the cell, one would
generally ensure that a significant period of time did not elapse
between the time of each delivery, such that the agent and
expression construct would still be able to exert an advantageously
combined effect on the cell. For example, in such instances, it is
contemplated that one may contact the cell, tissue or organism with
two, three, four or more modalities substantially simultaneously
(i.e., within less than about a minute) with the organic arsenical.
In other aspects, one or more agents may be administered within
about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes
about 30 minutes, about 45 minutes, about 60 minutes, about 2
hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours,
about 7 hours about 8 hours, about 9 hours, about 10 hours, about
11 hours, about 12 hours, about 13 hours, about 14 hours, about 15
hours, about 16 hours, about 17 hours, about 18 hours, about 19
hours, about 20 hours, about 21 hours, about 22 hours, about 23
hours, about 24 hours, about 25 hours, about 26 hours, about 27
hours, about 28 hours, about 29 hours, about 30 hours, about 31
hours, about 32 hours, about 33 hours, about 34 hours, about 35
hours, about 36 hours, about 37 hours, about 38 hours, about 39
hours, about 40 hours, about 41 hours, about 42 hours, about 43
hours, about 44 hours, about 45 hours, about 46 hours, about 47
hours, to about 48 hours or more prior to and/or after
administering the organic arsenical. In certain other embodiments,
an agent may be administered within of from about 1 day, about 2
days, about 3 days, about 4 days, about 5 days, about 6 days, about
7 days, about 8 days, about 9 days, about 10 days, about 11 days,
about 12 days, about 13 days, about 14 days, about 15 days, about
16 days, about 17 days, about 18 days, about 19 days, about 20, to
about 21 days prior to and/or after administering the organic
arsenical. In some situations, it may be desirable to extend the
time period for treatment significantly, however, where several
weeks (e.g., about 1, about 2, about 3, about 4, about 5, about 6,
about 7 or about 8 weeks or more) lapse between the respective
administrations.
[0137] Various combinations may be employed, the organic arsenical
is "A" and the secondary agent, which can be any other therapeutic
agent, is "B":
[0138] A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
[0139] B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
[0140] B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
[0141] Administration of the therapeutic compositions of the
present invention to a patient will follow general protocols for
the administration of chemotherapeutics, taking into account the
toxicity, if any. It is expected that the treatment cycles would be
repeated as necessary. It also is contemplated that various
standard therapies or adjunct cancer therapies, as well as surgical
intervention, may be applied in combination with the described
arsenical agent. These therapies include but are not limited to
chemotherapy, radiotherapy, immunotherapy, gene therapy and
surgery. The section below describes some adjunct cancer
therapies:
Chemotherapy
[0142] Cancer therapies also include a variety of combination
therapies with both chemical and radiation based treatments.
Combination chemotherapies include, for example, cisplatin (CDDP),
carboplatin, procarbazine, mechlorethamine, cyclophosphamide,
camptothecin, ifosfamide, melphalan, chlorambucil, busulfan,
nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin,
plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene,
estrogen receptor binding agents, taxol, gemcitabine, navelbine,
farnesyl-protein transferase inhibitors, transplatinum,
5-fluorouracil, vincristin, vinblastin and methotrexate, or any
analog or derivative variant of the foregoing.
Radiotherapy
[0143] Other factors that cause DNA damage and have been used
extensively include what are commonly known as .gamma.-rays,
X-rays, and/or the directed delivery of radioisotopes to tumor
cells. Other forms of DNA damaging factors are also contemplated
such as microwaves and UV-irradiation. It is most likely that all
of these factors effect a broad range of damage on DNA, on the
precursors of DNA, on the replication and repair of DNA, and on the
assembly and maintenance of chromosomes. Dosage ranges for X-rays
range from daily doses of 50 to 200 roentgens for prolonged periods
of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens.
Dosage ranges for radioisotopes vary widely, and depend on the
half-life of the isotope, the strength and type of radiation
emitted, and the uptake by the neoplastic cells. The terms
"contacted" and "exposed," when applied to a cell, are used herein
to describe the process by which a therapeutic construct and a
chemotherapeutic or radiotherapeutic agent are delivered to a
target cell or are placed in direct juxtaposition with the target
cell. To achieve cell killing or stasis, both agents are delivered
to a cell in a combined amount effective to kill the cell or
prevent it from dividing.
Immunotherapy
[0144] Immunotherapeutics, generally, rely on the use of immune
effector cells and molecules to target and destroy cancer cells.
The immune effector may be, for example, an antibody specific for
some marker on the surface of a tumor cell. The antibody alone may
serve as an effector of therapy or it may recruit other cells to
actually effect cell killing. The antibody also may be conjugated
to a drug or toxin (chemotherapeutic, radionucleotide, ricin A
chain, cholera toxin, pertussis toxin, etc.) and serve merely as a
targeting agent. Alternatively, the effector may be a lymphocyte
carrying a surface molecule that interacts, either directly or
indirectly, with a tumor cell target. Various effector cells
include cytotoxic T cells and NK cells.
[0145] Immunotherapy, thus, could be used as part of a combined
therapy, in conjunction with gene therapy. The general approach for
combined therapy is discussed below. Generally, the tumor cell must
bear some marker that is amenable to targeting, i.e., is not
present on the majority of other cells. Many tumor markers exist
and any of these may be suitable for targeting in the context of
the present invention. Common tumor markers include
carcinoembryonic antigen, prostate specific antigen, urinary tumor
associated antigen, fetal antigen, tyrosinase (p9'7), gp68, TAG-72,
HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor,
laminin receptor, erb B and p155.
Gene Therapy
[0146] In yet another embodiment, the secondary treatment is a
secondary gene therapy in which a therapeutic polynucleotide is
administered before, after, or at the same time a first therapeutic
agent. Delivery of the therapeutic agent in conjunction with a
vector encoding a gene product will have a combined
anti-hyperproliferative effect on target tissues.
[0147] Surgery
[0148] Approximately 60% of persons with cancer will undergo
surgery of some type, which includes preventative, diagnostic or
staging, curative and palliative surgery. Curative surgery is a
cancer treatment that may be used in conjunction with other
therapies, such as the treatment of the present invention,
chemotherapy, radiotherapy, hormonal therapy, gene therapy,
immunotherapy and/or alternative therapies. Curative surgery
includes resection in which all or part of cancerous tissue is
physically removed, excised, and/or destroyed. Tumor resection
refers to physical removal of at least part of a tumor. In addition
to tumor resection, treatment by surgery includes laser surgery,
cryosurgery, electrosurgery, and microscopically controlled surgery
(Mohs' surgery). It is further contemplated that the present
invention may be used in conjunction with removal of superficial
cancers, precancers, or incidental amounts of normal tissue.
EXAMPLES
[0149] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art will, in light of the present disclosure,
appreciate that many changes can be made in the specific
embodiments which are disclosed and still obtain a like or similar
result without departing from the spirit and scope of the
invention.
Example 1
Synthesis of S-dimethylarsino-thiosuccinic acid (MER1),
S-dimethylarsino-salicylic acid (SALT), and S-(dimethylarsino)
glutathione (SGLU1)
[0150] MER-1: Mercaptosuccinic acid, 4.5 g, was placed in 100 mL of
glyme (1,2-dimethoxyethane) in a 250 mL round-bottom flask. Four mL
of dimethylchloroarsine (0.03 mol) was added drop-wise, followed by
4 mL of diethylamine (0.04 mol), again dropwise. The reaction
mixture was stirred for 20 h at room temperature. A white
precipitate of diethylamine hydrochloride was formed and was
separated by filtration. The solution of MER1 in the glyme was
greatly reduced in volume by evaporation at reduced pressure. White
crystals of MER1 were separated by filtration and washed with cold
distilled water. The colorless crystalline product was then
recrystallized from ethanol-water to a constant melting point of
150.degree. C.
[0151] SAL-1: In a 100 ml, flask 5 g of 2-mercapto benzoic acid
(thiosalicylic acid), 75 mL of glyme, 5 mL of dimethylchloroarsine,
and 5 mL diethylamine were placed. The mixture was refluxed for 1
hour under an atmosphere of nitrogen and stirred at room
temperature overnight. The precipitate of diethylamine
hydrochloride was separated by filtration. The filtrate was
evaporated slowly under reduced pressure until crystals of the
product separate. The evaporated solution containing the product
was chilled in ice and the cold solution was filtered. Crystals of
the product were recrystallized from ethanol to a constant melting
point of 97.degree. C.
[0152] SGLU-1: Glutathione (14.0 g, 45.6 mmol) was stirred rapidly
in glyme while dimethylchoroarsine (6.5 g, 45.6 mmol) was added
dropwise. Pyridine (6.9 g, 91.2 mmol) was then added to the slurry
and the mixture was subsequently heated to reflux. The heat was
removed immediately and the mixture stirred at room temperature for
4 h. Isolation of the resultant insoluble solid and
recrystallization from ethanol afforded 4 as the pyridine
hydrochloride complex (75% yield): mp 115-118.degree. C.; NMR
(D.sub.2O) .delta.1.35 (s, 6H), 1.9-4.1 (m's, 10H), 7.8-9.0 (m,
5H); mass spectrum (m/e) 140, 125, 110, 105, 79, 52, 45, 36. This
material is not used for the examples described herein, but has
been used in biological assays as described in Banks, C. H., et al.
(J. Med. Chem. (1979) 22: 572-575), which is incorporated herein by
reference in its entirety.
Example 2
Alternate Synthesis of S-Dimethylarsinoglutathione
[0153] The following procedure describes the manner of preparation
of S-dimethylarsinoglutathione. The quantities used can be
multiplied or divided with equal success if the respective ratios
are maintained.
[0154] Dimethylchloroarsine.
[0155] Dimethylarsinic acid, (CH.sub.3).sub.2As(O)OH was supplied
by the Luxembourg Chemical Co., Tel Aviv, Israel. The product was
accompanied by a statement of its purity and was supplied as 99.7%
pure. The dimethylarsinic acid was dissolved in water-hydrochloric
acid to pH 3. A stream of sulfur dioxide was passed through this
solution for about one hour. Dimethylchloroarsine separated as a
heavy, colorless oil. The two liquid phases,
water/(CH.sub.3).sub.2AsCl were separated using a separatory
funnel. The chlorodimethylarsine was extracted into diethylether
and the ether solution was dried over anhydrous sodium sulfate. The
dried solution was transferred to a distillation flask which was
heated slowly to evaporate the ether. The remaining liquid,
dimethylchloroarsine was purified by distillation. The fraction
boiling at 106-109.degree. C. was collected. The product, a
colorless oil, displays a simple .sup.1H NMR resonance at 1.65
ppm.
[0156] S-Dimethylarsinoglutathione.
[0157] In a 500 mL flask, 7 g of glutathione was used as received
from the Aldrich Chemical Co., purity 98% and dissolved in 250 mL
of 1,2-dimethoxyethane. To this solution was added 3.3 g of
dimethylchloroarsine. This was followed by the addition of 3.5 g of
pyridine (redistilled after drying over NaOH pellets). The solution
was refluxed for one hour after which time it was stirred at room
temperature for three hours.
[0158] The desired product, S-dimethylarsinoglutathione was
separated as the pyridine hydrochloride complex. The solid was
removed by filtration and washed thoroughly with
1,2-dimethoxyethane. It was subsequently dried over anhydrous
calcium chloride in vacuo. The yield of S-dimethylarsinoglutathione
pyridine hydrochloride was 10.3 g and the melting point was
135-140.degree. C. This material was used in the biological assays
described above in examples 2 to 12.
Example 3
Pyridine Hydrochloride Free Synthesis of
S-dimethylarsinoglutathione (GLU)
[0159] Dimethylarsinoglutathione is made using an adapted of Chen
(Chen, G. C., et al. Carbohydrate Res. (1976) 50: 53-62) the
contents of which are hereby incorporated by reference in their
entirety. Briefly, dithiobis(dimethylarsinoglutamine) is dissolved
in dichloromethane under nitrogen. Tetramethyldiarsine is added
dropwise to the solution and the reaction is stirred overnight at
room temperature under nitrogen and then exposed to air for 1 h.
The mixture is then evaporated to dryness and the residue is washed
with water and dried to give a crude solid that is recrystallized
from methanol to give S-dimethylarsinoglutathione.
Example 4
Third Synthesis of Pyridine Hydrochloride Free
S-dimethylarsinoglutathione (GLU)
[0160] S-dimethylarsinoglutathione is made using the procedure of
Cullen et al. (J. Inorg. Biochem. (1984) 21: 179-194) the contents
of which are hereby incorporated by reference in their entirety.
Briefly, dimethylarsinic acid and glutathione are dissolved in
water under a nitrogen atmosphere and stirred. The resulting
solution is stirred for 12 h and then evaporated to dryness under
reduced pressure without heating to give a solid that is extracted
with cold methanol. The methanol solution is then evaporated to
dryness under reduced pressure and the resulting solid is
recrystallized from methanol/water, collected, and dried to give
S-dimethylarsinoglutathione.
Example 5
Preparation of Dimethylchloroarsine
[0161] A 3 L, 3 necked round bottom flask was equipped with a
mechanical stirrer assembly, an additional funnel, thermometer,
nitrogen inlet, and a drying tube was placed in a bath. The flask
was charged with cacodylic acid (250 g) and concentrated HCl (825
mL) and stirred to dissolve. After the cacodylic acid was
completely dissolved, the solution was warmed to 40.degree. C. To
the stirring solution, hypophosphorous acid (H.sub.3PO.sub.2) (50%
solution, 250 g) was added dropwise, maintaining the reaction
temperature between 40-50.degree. C. After approximately 50 mL of
H.sub.3PO.sub.2 had been added, the solution became cloudy and the
temperature of the reaction rose rapidly at which time an external
cooling bath was used to maintain the reaction temperature between
40-50.degree. C. The addition of the H.sub.3PO.sub.2 was continued,
maintaining the reaction temperature in the desired range. After
the addition of H.sub.3PO.sub.2 was complete, the reaction was held
between 40-45.degree. C. for 15 minutes while stirring. The
external bath was removed and the stirring was continued. The
reaction was allowed to stir and cool to <30.degree. C. After
the temperature of the reaction mixture dropped to 30.degree. C. or
less, methylene chloride (300 mL) was added and the resulting
mixture was stirred to extract the product into the methylene
chloride. Stirring was discontinued and the layers were allowed to
separate over 1/2 hour. The layers were separated and the methylene
chloride layer was dried over anhydrous sodium sulfate with
stirring for a minimum of 1 hour. The mixture may be allowed to sit
under a nitrogen atmosphere for a maximum of 72 hours. The organic
mixture was filtered to remove the sodium sulfate and the methylene
chloride was removed by atmospheric distillation. The crude
residual product was distilled under a nitrogen atmosphere, through
an 8'' Vigreux or packed column. The product fraction with by
104-106.degree. C. at atmospheric pressure was collected.
Preparation of S-Dimethylarsinoglutathione
[0162] A 5 L, three necked round bottom flask was equipped with a
mechanical stirrer assembly, thermometer, addition funnel, nitrogen
inlet, and a drying tube was placed in a cooling bath. A
polyethylene crock was charged with glutathione-reduced (200 g) and
deionized water (2 L) and stirred under a nitrogen atmosphere to
dissolve all solids. The mixture was filtered to remove any
insoluble material and the filtrate was transferred to the 5 L
flask. While stirring, ethanol, 200 proof (2 L) was added and the
clear solution was cooled to 0-5.degree. C. using an ice/methanol
bath. Pyridine (120 g) was added followed by a dropwise addition of
Me.sub.2AsCl (120 g) over a minimum of 1 hour. The reaction mixture
was stirred at 0-5.degree. C. for a minimum of 2 hours prior to
removal of the cooling bath and allowing the mixture to warm to
room temperature under a nitrogen atmosphere with stirring. The
reaction mixture was stirred overnight (>15 hrs) at room
temperature under a nitrogen atmosphere at which time a white solid
may precipitate. The reaction mixture was concentrated to a slurry
(liquid and solid) at 35-45.degree. C. using oil pump vacuum to
provide a white solid residue. As much water as possible is
removed, followed by two coevaporations with ethanol to azeotrope
the last traces of water. The white solid residue was slurried in
ethanol, 200 pf. (5 L) under a nitrogen atmosphere at room
temperature overnight. The white solid was filtered and washed with
ethanol, 200 pf. (2.times.500 mL) followed by acetone, ACS
(2.times.500 mL). The resulting solid was transferred to drying
trays and vacuum oven dried overnight at 25-35.degree. C. using oil
pump vacuum to provide pyridinium hydrochloride-free
S-dimethylarsinoglutathione as a white solid with a melting point
of 189-190.degree. C.
[0163] Preparation of Dosage Form of
S-Dimethylarsinoglutathione
[0164] A solution of S-dimethylarsinoglutathione in water for
injection (WFI) was adjusted to pH 5.0 to 5.5 with NaOH or HCl. The
resulting solution was then filtered through a 0.2 micron Sartopore
2 filter and a Flexicon filling unit was used to deliver 150 mg per
Type 1 borosilicate glass vial (Wheaton). The filled vials were
then lyophilized in a Hull 48 Lyophilizer unit by first loading the
vials on the shelf and ramping the temperature to -40.degree. C. at
a cooling rate of 0.5.degree. C. per minute. The shelf temperature
was then held at -40.degree. C. for 300 minutes. A vacuum was then
applied at 75 micron and the shelf temperature was ramped up to
5.degree. C. at a rate of 0.1.degree. C. per minute. The shelf
temperature was then held at 5.degree. C. for 1,000 minutes before
applying the vacuum at 50 micron. The shelf temperature was then
ramped up to 25.degree. C. at a rate of 0.1.degree. C. per minute
and the temperature was held at 25.degree. C. for 720 minutes. The
shelf temperature was then reduced to 5.degree. C. and held until
the final stoppering step, at which time the chamber was returned
to 640,000 mm Torr with nitrogen and the vials were stoppered with
gray butyl lyophilization stoppers and finally crimped with
aluminum seals to provide S-dimethylarsinoglutathione as a white to
off-white cake with a moisture content of 1.8%. The total time for
the lyophilization procedure was 47 hours. The lyophilized
S-dimethylarsinoglutathione was then reconstituted with 2.0 mL
sterile water to provide a clear, colorless solution with a final
concentration of 75.+-.7.5 mg S-dimethylarsinoglutathione per mL
and a pH of 4.5 to 6.0.
Example 6
Preparation of Dimethylchloroarsine (DMCA)
[0165] A 3-neck round-bottom flask (500 mL) equipped with
mechanical stirrer, inlet for nitrogen, thermometer, and an ice
bath was charged with cacodylic acid (33 g, 0.23 mol) and conc.
hydrochloric acid (67 mL). In a separate flask, a solution of
SnCl.sub.2.2 H.sub.2O (54 g, 0.239 mol) in conc. hydrochloric acid
(10 mL) was prepared. The SnCl.sub.2 .2 H.sub.2O solution was added
to the cacodylic acid in HCl solution under nitrogen while
maintaining the temperature between 5.degree. C. and 10.degree. C.
After the addition was complete, the ice bath was removed and the
reaction mixture was stirred at ambient temperature for 1 h. The
reaction mixture was transferred to a separatory funnel and the
upper layer (organic) collected. The bottom layer was extracted
with dichloromethane (DCM) (2.times.25 mL). The combined organic
extract was washed with 1 N HCl (2.times.10 mL) and water
(2.times.20 mL). The organic extract was dried over MgSO.sub.4 and
DCM was removed by rotary evaporation (bath temperature 80.degree.
C., under nitrogen, atmospheric pressure). The residue was further
distilled under nitrogen. Two fractions of DMCA were collected. The
first fraction contained some DCM and the second fraction was of
suitable quality (8.5 g, 26% yield). The GC analysis confirmed the
identity and purity of the product.
Preparation of S-Dimethylarsinoglutathione (SGLU-1)
[0166] A suspension of glutathione (18 g, 59 mmol) in a mixture of
water/ethanol 1:1 v/v (180 mL) was cooled below 5.degree. C. and
under an inert atmosphere treated with triethylamine (10 mL, 74
mmol) in one portion. The mixture was cooled to 0-5.degree. C. and
DMCA (11 g, 78.6 mmol) was added dropwise over a period of 10 min,
while maintaining the temperature below 5.degree. C. The reaction
mixture was stirred at 0-5.degree. C. for 4 h, and the resulting
solids were isolated by filtration. The product was washed with
ethanol (2.times.50 mL) and acetone (2.times.50 mL) and dried in
vacuum at RT overnight, to give 11 g (46%) of SGLU-1. HPLC purity
was 97.6% by area (average of 3 injections), Anal. Calcd. for
C.sub.12H.sub.22AsN.sub.3O.sub.6S: C, 35.04; H, 5.39; N, 10.12., S,
7.8. Found: C, 34.92; H, 5.31; N, 10.27., S, 7.68. .sup.1H and
.sup.13C-NMR were consistent with the structure. The filtrate was
diluted with acetone (150 mL) and placed in a refrigerator for 2
days. An additional 5.1 g (21%) of SGLU-1 was isolated as the
second crop, HPLC purity was 97.7% by area (average of 3
injections).
Preparation of S-Dimethylarsinoglutathione (SGLU-1)
[0167] In a 3 L three-neck flask equipped with a mechanic stirrer,
dropping funnel and thermometer under an inert atmosphere was
prepared a suspension of glutathione (114.5 g, 0.37 mol) in a 1:1
(v/v) mixture of water/ethanol (1140 mL) and cooled to below
5.degree. C. The mixture was treated slowly (over 15 min) with
triethylamine (63.6 mL, 0.46 mol) while maintaining the temperature
below 20.degree. C. The mixture was cooled to 4.degree. C. and
stirred for 15 min and then the traces of undissolved material
removed by filtration. The filtrate was transferred in a clean 3 L
three-neck flask equipped with a mechanic stirrer, dropping funnel,
nitrogen inlet, and thermometer and DMCA (70 g, 0.49 mol) (lot #
543-07-01-44) was added slowly while maintaining the temperature at
3-4.degree. C. The reaction mixture was stirred at 1-4.degree. C.
for 4 h, and acetone (1.2 L) was added over a period of 1 h. The
mixture was stirred for 90 min between 2 and 3.degree. C. and the
resulting solid was isolated by filtration. The product was washed
with ethanol (2.times.250 mL) and acetone (2.times.250 mL) and the
wet solids were suspended in ethanol 200 Proof (2000 mL). The
product was isolated by filtration, washed with ethanol
(2.times.250 mL) and acetone (2.times.250 mL) and dried in vacuum
for 2 days at RT to give 115 g (75%) of SGLU-1, HPLC purity
>99.5% (in process testing).
Example 7
In Vitro Evaluation of Anti Cancer Activity of GMZ27
[0168] GMZ27, an organic arsine having the following structure
##STR00017##
[0169] was tested in 72 hour MTS assays against different human
acute myelocytic leukemia (AML) cell lines and it was found that
the IC.sub.50 was 0.56-0.86 .mu.M. This activity was higher than
the activity of arsenic trioxide against these cell lines (FIG.
27A). The anti-leukemic activity of GMZ27 was then evaluated in a
long-term (7 day) colony-forming assay, where cells are grown in
semi-solid medium. GMZ27 had significantly higher activity than
arsenic trioxide against both human leukemia cell lines and
leukemic cells obtained from patients with acute or chronic
leukemia (FIG. 27B).
[0170] The mechanisms of anti-cancer activity of GMZ27 and arsenic
trioxide were then compared. Arsenic trioxide (ATO) exerted its
anti-leukemic activity in cells other than APL via several
mechanisms, including induction of apoptosis, alteration in the
production of intracellular ROS resulting in the modulation of
cellular GSH redox system, cell differentiation/maturation and
possible effect on cell cycle regulation.
[0171] GMZ27 was more potent in induction of apoptosis than ATO.
Results show that it activated the mitochondrial apoptotic pathway,
as it altered mitochondrial membrane potential and cleaved caspase
9, but also by alternate, extrinsic, pathway since it cleaved
caspase 8. This resulted in the induction of caspase 3 activity,
cleavage of PARP, and binding of annexin V to the cells (FIGS. 28
and 29).
[0172] Pretreatment of leukemic cells with buthionine
sulfoximine(BSO) renders them more sensitive to GMZ27; while
pretreatment with dthiothreitol (DTT) or N-acetylcysteine (NAC),
which may increase intracellular GSH, rendered the cells less
sensitive (FIG. 30). This suggested that GMZ27, like ATO, modulates
the GSH redox system in leukemic cells, however, it did so earlier
and to a greater extent than ATO did (FIG. 31).
[0173] GMZ27, at low doses, was found to partially induce cell
differentiation/maturation as judged by the induction of CD11b
maturation marker on the surface of cells. This effect was marginal
compared with that of ATO (FIG. 32). GMZ27 had no effect on the
cell cycle progression (FIG. 33).
[0174] Toxicity of GMZ7 against healthy donor peripheral blood
mononuclear cells has been evaluated in a long-term colony forming
assay. GMZ27 was less toxic to normal cells than ATO (FIG. 34).
[0175] Studies to determine the toxicity of a single dose injection
of GMZ27 were performed in normal Swiss-Webster mice. Toxicity was
measured on the basis of mortality. It was found that the
concentration of GMZ27 that kills 50% of mice (LD.sub.50) was 100
mg/kg. In contrast, the LD.sub.50 for ATO was much lower, at only
10 mg/kg.
Example 8
Preparation of N-(2-S-dimethylarsinothiopropionyl)glycine
[0176] N-(2-mercaptopropionyl)glycine (0.02 mol, 3.264 g) was
placed in 1,2-dimethoxyethane (50 mL) and dimethylchloroarsine
(0.025 mol, 3.52 g) was added dropwise. The reaction mixture was
stirred for 4 h at room temperature. A white precipitate of
triethylamine hydrochloride salt was then separated by filtration
and the solubtion was reduced in volume by evaporation at reduced
pressure. The resulting residue was purified by column
chromatography to afford the desired product (3.5 g).
Example 9
Preparation of 2-(S-dimethylarsino)thionicotinic acid
[0177] 2-Mercaptonicotinic acid (0.02 mol, 3 g) was placed in
dichloromethane (50 mL) and dimethylchloroarsine (0.025 mol, 3.52
g) was added dropwise. The reaction was stirred at reflux for 4 h.
The dichloromethane was then removed by distillation and the
residue was dissolved in diethyl ether (50 mL) and washed with
water (3.times.). The solution was dried over Na.sub.2SO.sub.4,
filtered, and the desired product was obtained as a pale yellow
solid after concentration under reduced pressure.
Example 10
L-(+)-2-amino-3-(dimethylarsino)thio-3-methylbutanoic acid
[0178] L-(+)-2-amino-3-mercapto-3-methylbutanoic acid (0.01 mol,
1.55 g) was placed in dichloromethane (50 mL) and
dimthylchloroarsine (0.015 mol, 2.1 g) in dichlorormethane (5 mL)
was added dropwise followed by the dropwise addition of
triethylamine (1.6 g). The mixture was stirred for 4 h and the
desired product appeared as a floating white crystalline solid
after filtration of the reaction mixture. The crystalline solid was
washed with dichloromethane, ethyl acetate, and acetone
sequentially to provide the desired product (1.6 g; mp
107-109.degree. C.).
Example 11
[0179] A Phase II multi-center trial of SGLU-1 (darinaparsin) was
conducted in patients diagnosed with advanced lymphomas. Eligible
patients required therapy and received at least 1 prior therapy.
Patients received 300 mg/m.sup.2 of darinaparsin intravenously for
5 consecutive days every 28 days (1 cycle) and were then evaluated
for efficacy and safety by standard criteria. Treatment continued
until toxicity or progression. To date the study has accrued 22
patients (15 non Hodgkin's [NHL], 7 Hodgkin's); 12 are male and 10
are female. Median age at baseline was 60.5 years (range: 28-80),
ECOG performance status was .ltoreq.2, and median number of prior
therapies was 3 (range: 1-6). Thirteen subjects have received at
least 2 cycles of SGLU-1 and are evaluable for efficacy. Of these,
1 (diagnosed with peripheral T-cell lymphoma (PTCL)) has achieved a
complete response (CR), 3 (diagnosed with diffuse large B-cell,
marginal zone, and Hodgkin's nodular sclerosis, respectively) have
achieved partial responses (PRs), and 2 patients with NHL have
achieved stable disease (SD). In the patient with marginal zone
lymphoma who achieved PR, no evidence for macroscopic disease was
present, but microscopic disease was detectable on random biopsies
from normal appearing gastric mucosa. All responders had been
heavily pretreated (PTCL: CHOP (cyclophosphamide, doxorubicin,
vincristine, and prednisolone).times.6, ICE (ifosfamide,
carboplatin and etoposide).times.1, and EPOCH (etoposide,
vincristine, doxorubicin, cyclophosphamide, and
prednisone).times.2; diffuse B-cell: RCHOP (rituximab,
cyclophosphamide, doxorubicin, vincristine, and
prednisolone).times.5, RICE (rituximab, ifosfamide, carboplatin and
etoposide).times.3, and radiation therapy; marginal zone:
rituximab.times.8, RCVP (rituximab, cyclophosphamide, vincristine
and prednisolone).times.1, and gemcitabine.times.1; and Hodgkin's:
ICE.times.1, CBV (cyclophosphamide, carmustine and
etoposide).times.1, gemcitabine+MDX-060 (Medarex).times.6). A total
of 49 cycles of SGLU-1 have been administered. The only Grade 3
adverse event (AE) considered drug-related was wheezing. A total of
12 subjects have reported 37 serious adverse events (SAEs) while on
study. Of these, only 2 had SAEs that were considered drug-related
(neutropenic fever, fall). In conclusion, SLGU-1 has been very well
tolerated and has demonstrated promising activity in heavily
pretreated patients diagnosed with advanced lymphoma. Initial
responses (1 CR, 3 PRs, 2 SDs) have been observed among 13
evaluable patients.
EQUIVALENTS
[0180] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the compounds and methods of use thereof described
herein. Such equivalents are considered to be within the scope of
this invention and are covered by the following claims. Those
skilled in the art will also recognize that all combinations of
embodiments described herein are within the scope of the
invention.
[0181] All of the above-cited references and publications are
hereby incorporated by reference.
* * * * *