U.S. patent application number 10/127956 was filed with the patent office on 2002-08-15 for inhibition of abnormal cell proliferation with camptothecin and combinations including the same.
Invention is credited to Rubinfeld, Joseph.
Application Number | 20020111362 10/127956 |
Document ID | / |
Family ID | 24210430 |
Filed Date | 2002-08-15 |
United States Patent
Application |
20020111362 |
Kind Code |
A1 |
Rubinfeld, Joseph |
August 15, 2002 |
Inhibition of abnormal cell proliferation with camptothecin and
combinations including the same
Abstract
A method for treating diseases associated with abnormal cell
proliferation comprises delivering to a patient in need of
treatment a compound selected from the group consisting of
20(S)-camptothecin, analog of 20(S)-camptothecin, derivative of
20(S)-camptothecin, prodrug of 20(S)-camptothecin, and
pharmaceutically active metabolite of 20(S)-camptothecin, in
combination with an effective amount of one or more agents selected
from the group consisting of alkylating agent, antibiotic agent, an
alkylating agent, antibiotic agent, antimetabolic agent, hormonal
agent, plant-derived agent, anti-angiogenesis agent and biologic
agent. The method can be used to treat benign tumors, malignant or
metastatic tumors, leukemia and diseases associated with abnormal
angiogenesis.
Inventors: |
Rubinfeld, Joseph;
(Danville, CA) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
943041050
|
Family ID: |
24210430 |
Appl. No.: |
10/127956 |
Filed: |
April 22, 2002 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10127956 |
Apr 22, 2002 |
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09553710 |
Apr 20, 2000 |
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09553710 |
Apr 20, 2000 |
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09418862 |
Oct 15, 1999 |
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6191119 |
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Current U.S.
Class: |
514/283 ;
424/94.63; 514/13.3; 514/171; 514/183; 514/19.6; 514/19.8;
514/20.9; 514/251; 514/263.32; 514/269; 514/317; 514/34; 514/492;
514/575; 514/733 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 31/4745 20130101; A61K 45/06 20130101; A61K 31/4745
20130101; A61K 31/44 20130101; A61K 31/70 20130101; A61K 31/70
20130101; A61K 31/44 20130101 |
Class at
Publication: |
514/283 ;
514/183; 514/34; 514/8; 514/251; 514/575; 514/263.32; 514/269;
514/492; 424/94.63; 514/317; 514/733; 514/171 |
International
Class: |
A61K 038/16; A61K
031/704; A61K 031/4745; A61K 038/48; A61K 038/14; A61K 031/33; A61K
031/525; A61K 031/522 |
Claims
What is claimed is:
1. A pharmaceutical composition having therapeutic synergy
comprising: a compound selected from the group consisting of 20(S)
-camptothecin, analog of 20(S)-camptothecin, derivative of 20(S)
-camptothecin, prodrug of 20(S)-camptothecin, and pharmaceutically
active metabolite of 20(S)-camptothecin; and one or more agents
selected from the group conisting of alkylating agent, antibiotic
agent, antimetabolic agent, hormonal agent, plant-derived agent,
anti-angiogenesis agent and biologic agent.
2. The pharmaceutical composition according to claim 1, wherein the
alkylating agent is selected from the group consisting of
bischloroethylamines, aziridines, alkyl alkone sulfonates,
nitrosoureas, nonclassic alkylating agents and platinum
compounds.
3. The pharmaceutical composition according to claim 1, wherein the
antibiotic agent is selected from the group consisting of
doxorubicin, daunorubicin, epirubicin, idarubicin and
anthracenedione, mitomycin C, bleomycin, dactinomycin, and
plicatomycin.
4. The pharmaceutical composition according to claim 1, wherein the
antimetabolic agent is selected from the group consisting of
fluorouracil, floxuridine, methotrexate, leucovorin, hydroxyurea,
thioguanine, mercaptopurine, cytarabine, pentostatin, fludarabine
phosphate, cladribine, asparaginase, and gemcitabine.
5. The pharmaceutical composition according to claim 1, wherein the
hormonal agent is selected from the group consisting of
diethylstibestrol, tamoxifen, toremifene, fluoxymesterol,
raloxifene, bicalutamide, nilutamide, flutamide, aminoglutethimide,
tetrazole, ketoconazole, goserelin acetate, leuprolide, megestrol
acetate and mifepristone.
5. The pharmaceutical composition according to claim 1, wherein the
plant-derived agent is selected from the group consisting of
vincristine, vinblastine, vindesine, vinzolidine, vinorelbine,
etoposide teniposide, paclitaxel and docetaxel.
6. The pharmaceutical composition according to claim 1, wherein the
biologic agent is selected from the group consisting of
immuno-modulating proteins, monoclonal antibodies against tumor
antigens, tumor suppressor genes, and cancer vaccines.
7. The pharmaceutical composition according to claim 6, wherein the
immuno-modulating protein is selected from the group consisting of
interleukin 2, interleukin 4, interleukin 12, interferon .alpha.,
interferon .beta., interferon .gamma., erythropoietin,
granulocyte-CSF, granulocyte, macrophage-CSF, bacillus
Calmette-Guerin, levamisole, and octreotide.
8. The pharmaceutical composition according to claim 6, wherein the
monoclonal antibody against tumor antigen is HERCEPTIN.RTM.
(Trastruzumab), or RITUXAN.RTM. (Rituximab).
9. The pharmaceutical composition according to claim 6, wherein the
tumor suppressor gene is selected from the group consisting of
DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA, and BRCA2.
10. The pharmaceutical composition according to claim 6, wherein
the cancer vaccine is selected from the group consisting of
gangliosides, prostate specific antigen, .alpha.-fetoprotein,
carcinoembryonic antigen, melanoma associated antigen MART-1,
gp100, papillomavirus E6 fragment, papillomavirus E7 fragment,
whole cells or portions/lysate of antologous tumor cells, and
allogeneic tumor cell.
11. The pharmaceutical composition according to claim 10 further
includes an adjuvant to augment the immune response to the cancer
vaccine.
12. The pharmaceutical composition according to claim 11, wherein
the adjuvant is selected from the group consisting of bacillus
Calmette-Guerin, endotoxin lipopolysaccharides, keyhole limpet
hemocyanin, interleukin-2, granulocyte-macrophage
colony-stimulating factor, and cytoxan.
13. The pharmaceutical composition according to claim 1, wherein
said composition is useful in the treatment of diseases associated
with abnormal cell proliferation or abnormal angiogenesis.
14. The pharmaceutical composition according to claim 1, wherein
the 20(S)-camptothecin is 9-amino-20(S)-camptothecin.
15. The pharmaceutical composition according to claim 1, wherein
the 20(S)-camptothecin is 9-nitro-20(S)-camptothecin.
16. A method for treating a disease associated with abnormal cell
proliferation, comprising: delivering to a patient suffering from
the disease a therapeutically effective amount of a compound
selected from the group consisting of 20(S)-camptothecin, analog of
20(S)-camptothecin, derivative of 20(S)-camptothecin, prodrug of
20(S)-camptothecin, and pharmaceutically active metabolite of
20(S)-camptothecin, in combination with an effective amount of one
or more agents selected from the group consisting of alkylating
agent, antibiotic agent, an alkylating agent, antibiotic agent,
antimetabolic agent, hormonal agent, plant-derived agent,
anti-angiogenesis agent and biologic agent.
17. The method according to claim 16, wherein the disease
associated with abnormal cell proliferation is selected from
restenosis, benign tumor, cancer, and atherosclerosis.
18. The method according to claim 16, wherein the benign tumor is
selected from the group consisting of hemangiomas, hepatocellular
adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic
neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma,
fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas,
nodular regenerative hyperplasia, trachomas and pyogenic
granulomas.
20. The method according to claim 16, wherein the cancer is
selected from the group consisting of leukemia, breast cancer, skin
cancer, bone cancer, prostate cancer, liver cancer, lung cancer,
brain cancer, cancer of the larynx, gallbladder, pancreas, rectum,
parathyroid, thyroid, adrenal, neural tissue, head and neck, colon,
stomach, bronchi, kidneys, basal cell carcinoma, squamous cell
carcinoma of both ulcerating and papillary type, metastatic skin
carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma,
myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet
cell tumor, primary brain tumor, acute and chronic lymphocytic and
granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia,
medullary carcinoma, pheochromocytoma, mucosal neuronms, intestinal
ganglloneuromas, hyperplastic corneal nerve tumor, marfanoid
habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater
tumor, cervical dysplasia and in situ carcinoma, neuroblastoma,
retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical
skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma,
osteogenic and other sarcoma, malignant hypercalcemia, renal cell
tumor, polycythermia Vera, adenocarcinoma, glioblastoma multiforma,
leukemias, lymphomas, malignant melanomas, and epidermoid
carcinomas.
21. A method for treating a disease associated with abnormal
angiogenesis, comprising: delivering to a patient suffering from
the disease a therapeutically effective amount of a compound
selected from the group consisting of 20(S)-camptothecin, analog of
20(S)-camptothecin, derivative of 20(S)-camptothecin, prodrug of
20(S)-camptothecin, and pharmaceutically active metabolite of
20(S)-camptothecin.
22. A method for treating a disease associated with abnormal
angiogenesis, comprising: delivering to a patient suffering from
the disease a therapeutically effective amount of a compound
selected from the group consisting of 20(S)-camptothecin, analog of
20(S)-camptothecin, derivative of 20(S)-camptothecin, prodrug of
20(S)-camptothecin, and pharmaceutically active metabolite of
20(S)-camptothecin in combination with an effective amount of one
or more anti-angiogenesis agents.
23. The method according to claim 22, wherein the anti-angiogenesis
agent is selected from the group consisting of retinoid acid,
2-methoxyestradiol, ANGIOSTATIN, ENDOSTATIN, suramin, squalamine,
tissue inhibitor of metalloproteinase-I, tissue inhibitor of
metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen
activator inhibitor-2, cartilage-derived inhibitor, paclitaxel,
platelet factor 4, protamine sulphate, sulphated chitin
derivatives, sulphated polysaccharide peptidoglycan complex,
staurosporine, L-azetidine-2-carboxylic acid, cis-hydroxyproline,
D, L.-3,4-dehydroproline, thiaproline, .alpha., .alpha.-dipyridyl,
.beta.-aminopropionitrile fumarate,
4-propyl-5-(4-pyridinyl)-2(3h)-oxazol- one, methotrexate,
mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3,
chymostatin, .beta.-cyclodextrin tetradecasulfate, eponemycin,
fumagillin, gold sodium thiomalate, D-penicillamine,
.beta.-1-anticollagenase-serum, .alpha.-2-antiplasmin, bisantrene,
lobenzarit disodium, n-(2-carboxyphenyl-4-chloroanthronilic acid
disodium or "CCA", thalidomide, angostatic steroid,
cargboxynaminolmidazole, metalloproteinase inhibitors, and
monoclonal antibodies against angiogenic growth factors.
24. The method according to claim 23, wherein the angiogenic growth
factor is selected from the group consisting of bFGF, aFGF, FGF-5,
VEGF-C, HGF/SF or Ang-1/Ang-2.
25. The method according to claim 22, wherein the disease
associated with abnormal angiogenesis is selected from the group
consisting of rheumatoid arthritis, ischemic-reperfusion related
brain edema and injury, cortical ischemia, ovarian hyperplasia and
hypervascularity, polycystic ovary syndrome, endometriosis,
psoriasis, diabetic retinopaphy, retinopathy of prematurity,
macular degeneration, corneal graft rejection, neuroscular
glaucoma, and Oster Webber syndrome.
26. A kit for treating a disease associated with abnormal cell
proliferation, comprising: a container that contains a compound
selected from the group consisting of 20(S)-camptothecin, analog of
20(S)-camptothecin, derivative of 20(S)-camptothecin, prodrug of
20(S)-camptothecin, and pharmaceutically active metabolite of
20(S)-camptothecin, and one or more agents selected from the group
consisting of alkylating agent, antibiotic agent, an alkylating
agent, antibiotic agent, antimetabolic agent, hormonal agent,
plant-derived agent, anti-angiogenesis agent and biologic
agent.
27. The kit according to claim 26, wherein the 20(S)-camptothecin
is 9-nitrocamptothecin, or 9-aminocamptothecin.
28. The kit according to claim 26, wherein the biological agent is
selected from the group consisting of immuno-modulating protein,
monoclonal antibody against tumor antigen, tumor suppressor gene,
and cancer vaccine.
Description
RELATIONSHIP TO COPENDING APPLICATIONS
[0001] This application claims priority to "COMBINATION THERAPY
INCLUDING CAMPTOTHECIN", application Ser. No.: 09/418,862; Filed:
Apr. 13, 1999 which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to a method for treating diseases
using a camptothecin, and more specifically a method for treating
diseases associated with abnormal cell growth using a camptothecin
alone or in combination with another drug.
DESCRIPTION OF RELATED ART
[0003] 20(S)-camptothecin, a plant alkaloid, was found to have
anticancer activity in the late 1950's. Wall, M. et al., Plant
antitumor agents. I. The isolation and structure of camptothecin, a
novel alkaloidal leukemia and tumor inhibitor from Camptotheca
acuminata, J. Am. Chem. Soc. 88: 3888-3890, (1966); Monroe E. Wall
et al., Camptothecin: Discovery to Clinic, 803 Annals of the New
York Academy of Sciences 1 (1996). These documents, and all
documents (articles, patents, etc.) cited to herein, are
incorporated by reference into the specification as if reproduced
fully below. The chemical formula of camptothecin was determined to
be C.sub.20H.sub.16N.sub.2O.sub.4.
[0004] 20(S)-camptothecin itself is insoluble in water. However,
during the sixties and seventies the sodium salt of
20(S)-camptothecin was derived from 20(S)-camptothecin through
opening of the lactone ring using a mild base. Clinical trials were
then conducted using this hydrosoluble, sodium salt derivative of
20(S)-camptothecin (20(S)-camptothecin Na+), which was administered
intravenously. The studies were later abandoned because of the high
toxicity and low potency of 20(S)-camptothecin Na.sup.+. Gottlieb,
J. A., et al., Preliminary pharmacological and clinical evaluation
of camptothecin sodium salt (NSC 100880), Cancer Chemother. Rep.
54:461-470 (1979); Muggia, F. M., et al., Phase I clinical trials
of weekly and daily treatment with camptothecin (NSC 100880):
Correlation with clinical studies, Cancer Chemother. Rep.
56:515-521 (1972); Gottlieb, J. A. et al., Treatment of malignant
melanoma with camptothecin (NSC 100880), Cancer Chemother. Rep.
56:103-105 (1972); and Moertel, C. G., et al., Phase II study of
camptothecin (NSC 100880) in the treatment of advanced
gastrointestinal cancer, Cancer Chemother Rep. 56:95-101
(1972).
[0005] Despite its potential, interest in 20(S)-camptothecin as a
therapeutic remained at a low ebb until the mid-1980's. By that
time, drug therapies were being evaluated for treating human cancer
using human cancer xenograft lines. During these evaluations, human
tumors are serially heterotransplanted into immunodeficient,
so-called nude mice, and the mice then tested for their
responsiveness to a specific drug. (Giovanella, B. C., et al.,
Cancer 52(7): 1146 (1983)). The data obtained in these studies
strongly support the validity of heterotransplanted human tumors
into immunodeficient mammals, such as nude mice, as a predictive
model for testing the effectiveness of anticancer agents.
[0006] 20(S)-camptothecin, and later some of its substituted forms,
elicited differential responses in the cell cycle of nontumorigenic
and tumorigenic human cells in vitro. Although it is not yet
understood why 20(S)-camptothecin and some of its substituted forms
are cytostatic for nontumorigenic cells and cytotoxic for
tumorigenic cells, the selective toxicity of the compounds against
tumorigenic cells in vitro and in vivo was an especially
interesting feature of these drugs.
[0007] Investigators began to experiment with various substituted
forms of 20(S)-camptothecin. Good activity was found when various
substitutions were made to the 20(S)-camptothecin scaffold. For
example, 9-Amino-20(S)-Camptothecin (9AC) and
10,11-Methylendioxy-20(S)-Camptothec- in (10,11 MD) are capable of
having high anticancer activity against human colon cancer
xenografts. Giovanella, B. C., et al., Highly effective
topoisomerase-I targeted chemotherapy of human colon cancer in
xenografts, Science, 246:1046-1048 (1989).
[0008] Additionally, 9-nitrocamptothecin (9NC) has shown high
activity against human tumor xenograft models. 9NC has a nine
position hydrogen substituted with a nitro moiety. 9NC has
inhibited the growth of human tumor xenografts in immunodeficient
nude mice and has induced regression of human tumors established as
xenografts in nude mice with little or no appearance of any
measurable toxicity. D. Chatterjee et al., Induction of Apoptosis
in Malignant and Camptothecin-resistant Human Cells, 803 Annals of
the New York Academy of Sciences 143 (1996).
[0009] U.S. Pat. No. 5,552,154 to Giovanella et al. disclosed
methods of treating specific forms of cancer with water-insoluble
20(S)-camptothecin and derivatives thereof, having the
closed-lactone ring intact. In particular, transdermal, oral and
intramuscular methods of administration using solutions of
water-insoluble 20(S)-camptothecin were disclosed.
[0010] Other substituted 20(S)-camptothecin compounds that have
shown promise include 7-ethyl-10-hydroxy 20(S)-camptothecin, and
other 7, 9, 10, 11-substituted compounds.
[0011] A continuing need exists to develop new and improved ways to
exploit the useful therapeutic activities of 20(S)-camptothecin and
its various derivatives and analogs.
SUMMARY OF THE INVENTION
[0012] The present invention provide new and improved compositions,
kits, and methods for treating diseases using a combination therapy
which includes 20(S)-camptothecin, an analog of 20(S)-camptothecin,
a derivative of 20(S)-camptothecin, a prodrug of
20(S)-camptothecin, or a pharmaceutically active metabolite of
20(S)-camptothecin, collectively referred to herein as CPT. A
therapeutic agent which exhibits a therapeutic synergistic effect
with CPT is preferably employed in the therapy.
[0013] A wide variety of non-CPT therapeutic agents with
therapeutic synergistic effects with CPT may be employed. Examples
of the non-CPT therapeutic agent include, but are not limited to,
alkylating agents, antibiotic agents, antimetabolic agents,
hormonal agents, plant-derived agents, and biologic agents.
[0014] Examples of alkylating agents include, but are not limited
to, bischloroethylamines (nitrogen mustards, e.g. chlorambucil,
cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil
mustard), aziridines (e.g. thiotepa), alkyl alkone sulfonates (e.g.
busulfan), nitrosoureas (e.g. carmustine, lomustine, streptozocin),
nonclassic alkylating agents (altretamine, dacarbazine, and
procarbazine), platinum compounds (carboplastin and cisplatin).
[0015] Examples of antibiotic agents include, but are not limited
to, anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin,
idarubicin and anthracenedione), mitomycin C, bleomycin,
dactinomycin, plicatomycin.
[0016] Examples of antimetabolic agents include, but are not
limited to, fluorouracil (5-FU), floxuridine (5-FUdR),
methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG),
mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine
phosphate, cladribine (2-CDA), asparaginase, and gemcitabine.
[0017] Examples of such hormonal agents are synthetic estrogens
(e.g. diethylstibestrol), antiestrogens (e.g. tamoxifen,
toremifene, fluoxymesterol and raloxifene), antiandrogens
(bicalutamide, nilutamide, flutamide), aromatase inhibitors (e.g.,
aminoglutethimide, anastrozole and tetrazole), ketoconazole,
goserelin acetate, leuprolide, megestrol acetate and
mifepristone.
[0018] Examples of plant-derived agents include, but are not
limited to, vinca alkaloids (e.g., vincristine, vinblastine,
vindesine, vinzolidine and vinorelbine), podophyllotoxins (e.g.,
etoposide (VP-16) and teniposide (VM-26)), taxanes (e.g.,
paclitaxel and docetaxel).
[0019] Examples of biologic agents include, but are not limited to,
immuno-modulating proteins such as cytokines, monoclonal antibodies
against tumor antigens, tumor suppressor genes, and cancer
vaccines.
[0020] Examples of interleukins that may be used in conjunction
with CPT include, but are not limited to, interleukin 2 (IL-2), and
interleukin 4 (IL-4), interleukin 12 (IL-12). Examples of
interferons that may be used in conjunction with CPT include, but
are not limited to, interferon .alpha., interferon .beta.
(fibroblast interferon) and interferon .gamma. (fibroblast
interferon). Examples of such cytokines include, but are not
limited to erythropoietin (epoietin .alpha.), granulocyte-CSF
(filgrastin), and granulocyte, macrophage-CSF (sargramostim). Other
immuno-modulating agents other than cytokines include, but are not
limited to bacillus Calmette-Guerin, levamisole, and
octreotide.
[0021] Example of monoclonal antibodies against tumor antigens that
can be used in conjunction with CPT include, but are not limited
to, HERCEPTIN.RTM. (Trastruzumab) and RITUXAN.RTM. (Rituximab).
[0022] Examples of the tumor suppressor genes include, but are not
limited to, DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA1 and BRCA2.
[0023] Example of cancer vaccines include, but are not limited to
gangliosides (GM2), prostate specific antigen (PSA),
.alpha.-fetoprotein (AFP), carcinoembryonic antigen (CEA) (produced
by colon cancers and other adenocarcinomas, e.g. breast, lung,
gastric, and pancreas cancers), melanoma associated antigens
(MART-1, gp100, MAGE 1,3 tyrosinase), papillomavirus E6 and E7
fragments, whole cells or portions/lysates of antologous tumor
cells and allogeneic tumor cells.
[0024] An adjuvant may be used to augment the immune response to
TAAs. Examples of adjuvants include, but are not limited to,
bacillus Calmette-Guerin (BCG), endotoxin lipopolysaccharides,
keyhole limpet hemocyanin (GKLH), interleukin-2 (IL-2),
granulocyte-macrophage colony-stimulating factor (GM-CSF) and
cytoxan, a chemotherapeutic agent which is believe to reduce
tumor-induced suppression when given in low doses.
[0025] The present invention also provides a method for treating
undesired or uncontrolled angiogenesis. In one embodiment, the
method comprises administering to a patient suffering from
uncontrolled angiogenesis a therapeutically effective amount of
CPT, such that formation of blood vessels is inhibited. In another
embodiment, the method comprises administering to a patient
suffering from uncontrolled angiogenesis a therapeutically
effective amount of CPT and one or more non-CPT anti-angiogenesis
agent, such that formation of blood vessels is inhibited.
embodiment,
[0026] Examples of non-CPT anti-angiogenesis agents include, but
are not limited to, retinoid acid and derivatives thereof,
2-methoxyestradiol, ANGIOSTATIN.TM. protein, ENDOSTATIN.TM.
protein,suramin, squalamine, tissue inhibitor of
metalloproteinase-I, tissue inhibitor of metalloproteinase-2,
plasminogen activator inhibitor-1, plasminogen activator
inhibitor-2, cartilage-derived inhibitor, paclitaxel, platelet
factor 4, protamine sulphate (clupeine), sulphated chitin
derivatives (prepared from queen crab shells), sulphated
polysaccharide peptidoglycan complex (sp-pg), staurosporine,
modulators of matrix metabolism, including for example, proline
analogs ((I-azetidine-2-carboxylic acid (LACA), cishydroxyproline,
d,l-3,4-dehydroproline, thiaproline],.alpha.,.alpha.-dipyridyl,
.beta.-aminopropionitrile fumarate,
4-propyl-5(4-pyridinyl)-2(3h)-oxazolone; methotrexate,
mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3,
chymostatin, beta.-cyclodextrin tetradecasulfate, eponemycin;
fumagillin, gold sodium thiomalate, d-penicillamine (CDPT),
beta.-1-anticollagenase-s- erum, alpha.2-antiplasmin, bisantrene,
lobenzarit disodium, n-(2-carboxyphenyl-4-chloroanthronilic acid
disodium or "CCA", thalidomide; angostatic steroid,
cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94.
Other anti-angiogenesis agents include antibodies, such as
monoclonal antibodies against these angiogenic growth factors:
bFGF, aFGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and
Ang-1/Ang-2.
[0027] The method may be used to treat a wide variety of
indications for which CPT has therapeutic activity. Such
indications include, but are not limited to, restenosis (e.g.
coronary, carotid, and cerebral lesions), benign tumors, a various
types of cancers such as primary tumors and tumor metastasis,
abnormal stimulation of endothelial cells (atherosclerosis),
insults to body tissue due to surgery, abnormal wound healing,
abnormal angiogenesis, diseases that produce fibrosis of tissue,
repetitive motion disorders, disorders of tissues that are not
highly vascularized, and proliferative responses associated with
organ transplants.
[0028] Examples of benign tumors include hemangiomas,
hepatocellular adenoma, cavernous haemangioma, focal nodular
hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma,
bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas,
teratomas, myxomas, nodular regenerative hyperplasia, trachomas and
pyogenic granulomas.
[0029] Specific types of cancers include, but are not limited to,
leukemia, breast cancer, skin cancer, bone cancer, prostate cancer,
liver cancer, lung cancer, brain cancer, cancer of the larynx,
gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal,
neural tissue, head and neck, colon, stomach, bronchi, kidneys,
basal cell carcinoma, squamous cell carcinoma of both ulcerating
and papillary type, metastatic skin carcinoma, osteo sarcoma,
Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor,
small-cell lung tumor, gallstones, islet cell tumor, primary brain
tumor, acute and chronic lymphocytic and granulocytic tumors,
hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma,
pheochromocytoma, mucosal neuronms, intestinal ganglloneuromas,
hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's
tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical
dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma,
soft tissue sarcoma, malignant carcinoid, topical skin lesion,
mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic
and other sarcoma, malignant hypercalcemia, renal cell tumor,
polycythermia vera, adenocarcinoma, glioblastoma multiforma,
leukemias, lymphomas, malignant melanomas, epidermoid carcinomas,
and other carcinomas and sarcomas.
[0030] Diseases associated with abnormal angiogenesis include, but
are not limited to, rheumatoid arthritis, ischemic-reperfusion
related brain edema and injury, cortical ischemia, ovarian
hyperplasia and hypervascularity, (polycystic ovary syndrom),
endometriosis, psoriasis, diabetic retinopaphy, and other ocular
angiogenic diseases such as retinopathy of prematurity (retrolental
fibroplastic), macular degeneration, corneal graft rejection,
neuroscular glaucoma and Oster Webber syndrome.
[0031] Examples of retinal/choroidal neuvascularization include,
but are not limited to, Bests diseases, myopia, optic pits,
Stargarts diseases, Pagets disease, vein occlusion, artery
occlusion, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma
elasticum carotid abostructive diseases, chronic uveitis/vitritis,
mycobacterial infections, Lyme's disese, systemic lupus
erythematosis, retinopathy of prematurity, Eales disease, diabetic
retinopathy, macular degeneration, Bechets diseases, infections
causing a retinitis or chroiditis, presumed ocular histoplasmosis,
pars planitis, chronic retinal detachment, hyperviscosity
syndromes, toxoplasmosis, trauma and post-laser complications,
diseases associated with rubesis (neovascularization of the angle)
and diseases caused by the abnormal proliferation of fibrovascular
or fibrous tissue including all forms of proliferative
vitreoretinopathy.
[0032] Examples of corneal neuvascularization include, but are not
limited to, epidemic keratoconjunctivitis, Vitamin A deficiency,
contact lens overwear, atopic keratitis, superior limbic keratitis,
pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis,
diabetic retinopathy, retinopathy of prematurity, corneal graft
rejection, Mooren ulcer, Terrien's marginal degeneration, marginal
keratolysis, polyarteritis, Wegener sarcoidosis, Scleritis,
periphigoid radial keratotomy, neovascular glaucoma and retrolental
fibroplasia, syphilis, Mycobacteria infections, lipid degeneration,
chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex
infections, Herpes zoster infections, protozoan infections and
Kaposi sarcoma.
DETAILED DESCRIPTION OF THE INVENTION
1. Camptothecin Compounds (CPT)
[0033] The class of camptothecin compounds referred to herein as
CPT include various 20(S)-camptothecins, analogs of 20(S)
-camptothecin, derivatives of 20(S)-camptothecin, prodrugsof
20(S)-camptothecin, and pharmaceutically active metabolites of
20(S)-camptothecin. Camptothecin, when used in the context of this
invention, includes the plant alkaloid 20(S)-camptothecin, both
substituted and unsubstituted camptothecins, and analogs thereof.
Examples of camptothecin derivatives include, but are not limited
to, 9-nitro-20(S)-camptothecin, 9-amino-20(S)-camptothecin,
9-methyl-camptothecin, 9-chloro-camptothecin,
9-flouro-camptothecin, 7-ethyl camptothecin,
10-methyl-camptothecin, 10-chloro--camptothecin,
10-bromo-camptothecin, 10-fluoro-camptothecin,
9-methoxy-camptothecin, 11-fluoro-camptothecin, 7-ethyl-10-hydroxy
camptothecin, 10,11-methylenedioxy camptothecin, and
10,11-ethylenedioxy camptothecin, and
7-(4-methylpiperazinomethylene)-10,11-methylenedioxy camptothecin.
Prodrugs of camptothecin include, but are not limited to,
esterified camptothecin derivatives as described in U.S. Pat. No.
5,731,316, such as camptothecin 20-O-propionate, camptothecin
20-O-butyrate, camptothecin 20-O-valerate, camptothecin
20-O-heptanoate, camptothecin 20-O-nonanoate, camptothecin
20-O-crotonate, camptothecin 20-O-2',3'-epoxy-butyrate,
nitrocamptothecin 20-O-acetate, nitrocamptothecin 20-O-propionate,
and nitrocamptothecin 20-O-butyrate.
[0034] In particular, when substituted camptothecins are used, a
large range of substitutions may be made to the camptothecin
scaffold, while still retaining activity. In a preferable
embodiment, the camptothecin scaffold is substituted at the 7, 9,
10, 11, and/or 12 positions. Such preferable substitutions may
serve to provide differential activities over the unsubstituted
camptothecin compound. Especially preferable are
9-nitrocamptothecin, 9-aminocamptothecin,
10,11-methylendioxy-20(S)-campt- othecin, topotecan, irinotecan,
7-ethyl-10-hydroxy camptothecin, or another substituted
camptothecin that is substituted at least one of the 7, 9, 10, 11,
or 12 positions.
[0035] Native, unsubstituted, camptothecin can be obtained by
purification of the natural extract, or may be obtained from the
Stehlin Foundation for Cancer Research (Houston, Tex.). Substituted
camptothecins can be obtained using methods known in the
literature, or can be obtained from commercial suppliers. For
example, 9-nitrocamptothecin may be obtained from SuperGen, Inc.
(San Ramon, Calif.), and 9-aminocamptothecin may be obtained from
Idec Pharmaceuticals (San Diego, Calif.). Camptothecin and various
of its analogs may also be obtained from standard fine chemical
supply houses, such as Sigma Chemicals.
[0036] Particular examples of 20(S)-camptothecins include
9-nitrocamptothecin, 9-aminocamptothecin,
10,11-methylendioxy-20(S)-campt- othecin, topotecan, irinotecan,
7-ethyl-10-hydroxy camptothecin, or another substituted
camptothecin that is substituted at least one of the 7, 9, 10, 11,
or 12 positions. These camptothecins may optionally be
substituted.
2. Non-CPT Therapeutic Agents
[0037] A wide variety non-CPT therapeutic agents may have a
therapeutic additive or synergistic effect with CPT. Such non-CPT
therapeutic agents may be hyperplastic inhibitory agents that
addictively or synergistically combine with CPT to inhibit
undesirable cell growth, such as inappropriate cell growth
resulting in undesirable benign conditions or tumor growth.
Examples of such non-CPT therapeutic agents include, but are not
limited to, alkylating agents, antibiotic agents, antimetabolic
agents, hormonal agents, plant-derived agents, and biologic
agents.
[0038] The alkylating agents are polyfunctional compounds that have
the ability to substitute alkyl groups for hydrogen ions. Examples
of alkylating agents include, but are not limited to,
bischloroethylamines (nitrogen mustards, e.g. chlorambucil,
cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil
mustard), aziridines (e.g. thiotepa), alkyl alkone sulfonates (e.g.
busulfan), nitrosoureas (e.g. carmustine, lomustine, streptozocin),
nonclassic alkylating agents (altretamine, dacarbazine, and
procarbazine), platinum compounds (carboplastin and cisplatin).
These compounds react with phosphate, amino, hydroxyl, sulfihydryl,
carboxyl, and imidazole groups. Under physiological conditions,
these drugs ionize and produce positively charged ion that attach
to susceptible nucleic acids and proteins, leading to cell cycle
arrest and/or cell death. Combination therapy including CPT and the
alkylating agent may have therapeutic synergistic effects on cancer
and reduce sides affects associated with these chemotherapeutic
agents.
[0039] The antibiotic agents are a group of drugs that produced in
a manner similar to antibiotics as a modification of natural
products. Examples of antibiotic agents include, but are not
limited to, anthracyclines (e.g. doxorubicin, daunorubicin,
epirubicin, idarubicin and anthracenedione), mitomycin C,
bleomycin, dactinomycin, plicatomycin. These antibiotic agents
interferes with cell growth by targeting different cellular
components. For example, anthracyclines are generally believed to
interfere with the action of DNA topoisomerase II in the regions of
transcriptionally active DNA, which leads to DNA strand scissions.
Bleomycin is generally believed to chelate iron and forms an
activated complex, which then binds to bases of DNA, causing strand
scissions and cell death. Combination therapy including CPT and the
antibiotic agent may have therapeutic synergistic effects on cancer
and reduce sides affects associated with these chemotherapeutic
agents.
[0040] The antimetabolic agents are a group of drugs that interfere
with metabolic processes vital to the physiology and proliferation
of cancer cells. Actively proliferating cancer cells require
continuous synthesis of large quantities of nucleic acids,
proteins, lipids, and other vital cellular constituents. Many of
the antimetabolites inhibit the synthesis of purine or pyrimidine
nucleosides or inhibit the enzymes of DNA replication. Some
antimetabolites also interfere with the synthesis of
ribonucleosides and RNA and/or amino acid metabolism and protein
synthesis as well. By interfering with the synthesis of vital
cellular constituents, antimetabolites can delay or arrest the
growth of cancer cells. Examples of antimetabolic agents include,
but are not limited to, fluorouracil (5-FU), floxuridine (5-FUdR),
methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG),
mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine
phosphate, cladribine (2-CDA), asparaginase, and gemcitabine.
Combination therapy including CPT and the antimetabolic agent may
have therapeutic synergistic effects on cancer and reduce sides
affects associated with these chemotherapeutic agents.
[0041] The hormonal agents are a group of drug that regulate the
growth and development of their target organs. Most of the hormonal
agents are sex steroids and their derivatives and analogs thereof,
such as estrogens, androgens, and progestins. These hormonal agents
may serve as antagonists of receptors for the sex steroids to down
regulate receptor expression and transcription of vital genes.
Examples of such hormonal agents are synthetic estrogens (e.g.
diethylstibestrol), antiestrogens (e.g. tamoxifen, toremifene,
fluoxymesterol and raloxifene), antiandrogens (bicalutamide,
nilutamide, flutamide), aromatase inhibitors (e.g.,
aminoglutethimide, anastrozole and tetrazole), ketoconazole,
goserelin acetate, leuprolide, megestrol acetate and mifepristone.
Combination therapy including CPT and the hormonal agent may have
therapeutic synergistic effects on cancer and reduce sides affects
associated with these chemotherapeutic agents.
[0042] Plant-derived agents are a group of drugs that are derived
from plants or modified based on the molecular structure of the
agents. Examples of plant-derived agents include, but are not
limited to, vinca alkaloids (e.g., vincristine, vinblastine,
vindesine, vinzolidine and vinorelbine), podophyllotoxins (e.g.,
etoposide (VP-16) and teniposide (VM-26)), taxanes (e.g.,
paclitaxel and docetaxel). These plant-derived agents generally act
as antimitotic agents that bind to tubulin and inhibit mitosis.
Podophyllotoxins such as etoposide are believed to interfere with
DNA synthesis by interacting with topoisomerase II, leading to DNA
strand scission. Combination therapy including CPT and the
plant-derived agent may have therapeutic synergistic effects on
cancer and reduce sides affects associated with these
chemotherapeutic agents.
[0043] Biologic agents are a group of biomolecules that elicit
cancer/tumor regression when used alone or in combination with
chemotherapy and/or radiotherapy. Examples of biologic agents
include, but are not limited to, immuno-modulating proteins such as
cytokines, monoclonal antibodies against tumor antigens, tumor
suppressor genes, and cancer vaccines. Combination therapy
including CPT and the biologic agent may have therapeutic
synergistic effects on cancer, enhance the patient's immune
responses to tumorigenic signals, and reduce potential sides
affects associated with this chemotherapeutic agent.
[0044] Cytokines possess profound immuno-modulatory activity. Some
cytokines such as interleukin-2 (IL-2, aldesleukin) and interferon
.alpha. (IFN-.alpha.) demonstrated antitumor activity and have been
approved for the treatment of patients with metastatic renal cell
carcinoma and metastatic malignant melanoma. IL-2 is a T-cell
growth factor that is central to T-cell-mediated immune responses.
The selective antitumor effects of IL-2on some patients are
believed to be the result of a cell-mediated immune response that
discriminate between self and nonself. Examples of interleukins
that may be used in conjunction with CPT include, but are not
limited to, interleukin 2 (IL-2), and interleukin 4 (IL-4),
interleukin 12 (IL-12).
[0045] Interferon .alpha. include more than 23 related subtypes
with overlapping activities, all of the IFN-.alpha. subtypes within
the scope of the present invention. IFN-.alpha. has demonstrated
activity against many solid and hematologic malignancies, the later
appearing to be particularly sensitive. Examples of interferons
that may be used in conjunction with CPT include, but are not
limited to, interferon .alpha., interferon .beta. (fibroblast
interferon) and interferon .gamma. (fibroblast interferon).
[0046] Other cytokines that may be used in conjunction with CPT
include those cytokines that exert profound effects on
hematopoiesis and immune functions. Examples of such cytokines
include, but are not limited to erythropoietin (epoietin .alpha.),
granulocyte-CSF (filgrastin), and granulocyte, macrophage-CSF
(sargramostim). These cytokines may be used in conjunction with CPT
to reduce chemotherapy-induced myelopoletic toxicity.
[0047] Other immuno-modulating agents other than cytokines may also
be used in conjunction with CPT to inhibit abnormal cell growth.
Examples of such immuno-modulating agents include, but are not
limited to bacillus Calmette-Guerin, levamisole, and octreotide, a
long-acting octapeptide that mimics the effects of the naturally
occuring hormone somatostatin.
[0048] Monoclonal antibodies against tumor antigens are antibodies
elicited against antigens expressed by tumors, preferably
tumor-specific antigens. For example, monoclonal antibody
HERCEPTIN.RTM. (Trastruzumab) is raised against human epidermal
growth factor receptor2 (HER2) that is overexpressed in some breast
tumors including metastatic breast cancer. Overexpression of HER2
protein is associated with more aggressive disease and poorer
prognosis in the clinic. HERCEPTIN.RTM. is used as a single agent
for the treatment of patients with metastatic breast cancer whose
tumors over express the HER2 protein. Combination therapy including
CPT and HERCEPTIN.RTM. may have therapeutic synergistic effects on
tumors, especially on metastatic cancers.
[0049] Another example of monoclonal antibodies against tumor
antigens is RITUXAN.RTM. (Rituximab) that is raised against CD20 on
lymphoma cells and selectively deplete normal and maligant
CD20.sup.+ pre-B and mature B cells. RITUXAN.RTM. is used as single
agent for the treatment of patients with relapsed or refractory
low-grade or follicular, CD20+, B cell non-Hodgkin's lymphoma.
Combination therapy including CPT and RITUXAN.RTM. may have
therapeutic synergistic effects not only on lymphoma, but also on
other forms or types of malignant tumors.
[0050] Tumor suppressor genes are genes that function to inhibit
the cell growth and division cycles, thus preventing the
development of neoplasia. Mutions in tumor suppressor genes cause
the cell to ignore one or more of the components of the network of
inhibitory signals, overcoming the cell cycle check points and
resulting in a higher rate of controlled cell growth--cancer.
Examples of the tumor suppressor genes include, but are not limited
to, DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA1 and BRCA2.
[0051] DPC-4 is involved in pancreatic cancer and participates in a
cytoplasmic pathway that inhibits cell division. NF-1 codes for a
protein that inhibits Ras, a cytoplasmic inhibitory protein. NF-1
is involved in neurofibroma and pheochromocytomas of the nervous
system and myeloid leukemia. NF-2 encodes a nuclear protein that is
involved in meningioma, schwanoma, and ependymoma of the nervous
system. RB codes for the pRB protein, a nuclear protein that is a
major inhibitor of cell cycle. RB is involved in retinoblastoma as
well as bone, bladder, small cell lung and breast cancer. P53 codes
for p53 protein that regulates cell division and can induce
apoptosis. Mutation and/or inaction of p53 is found in a wide
ranges of cancers. WT1 is involved in Wilms tumor of the kidneys.
BRCA1 is involved in breast and ovarian cancer, and BRCA2 is
involved in breast cancer. The tumor suppressor gene can be
transferred into the tumor cells where it exerts its tumor
suppressing functions. Combination therapy including CPT and tumor
suppressor may have therapeutic synergistic effects on patients
suffering from various forms of cancers.
[0052] Cancer vaccines are a group of agents that induce the body's
specific immune response to tumors. Most of cancer vaccines under
research and development and clinical trials are tumor-associated
antigens (TAAs). TAA are structures (i.e. proteins, enzymes or
carbohydrates) which are present on tumor cells and relatively
absent or diminished on normal cells. By virtue of being fairly
unique to teh tumor cell, TAAs provide targets for the immune
system to recognize and cause their destruction. Example of TAAs
include, but are not limited to gangliosides (GM2), prostate
specific antigen (PSA), .alpha.-fetoprotein (AFP), carcinoembryonic
antigen (CEA) (produced by colon cancers and other adenocarcinomas,
e.g. breast, lung, gastric, and pancreas cancer s), melanoma
associated antigens (MART-1, gp100, MAGE 1,3 tyrosinase),
papillomavirus E6 and E7 fragments, whole cells or portions/lysates
of antologous tumor cells and allogeneic tumor cells.
[0053] An adjuvant may be used to augment the immune response to
TAAs. Examples of adjuvants include, but are not limited to,
bacillus Calmette-Guerin (BCG), endotoxin lipopolysaccharides,
keyhole limpet hemocyanin (GKLH), interleukin-2 (IL-2),
granulocyte-macrophage colony-stimulating factor (GM-CSF) and
cytoxan, a chemotherapeutic agent which is believe to reduce
tumor-induced suppression when given in low doses.
[0054] A combination therapy including CPT and cancer vaccines may
have therapeutic synergistic effects on tumors, which would
potentially reduce the dosage of CPT needed for effective
treatment. Thus, side effects associatec with non-specific
cytotoxicity due to high doses of chemotherapeutic agent can be
reduced.
3. Indications for Treatment with CPT
[0055] Preferable indications that may be treated using the
combination therapies of the present invention include those
involving undesirable or uncontrolled cell proliferation. Such
indications include restenosis (e.g. coronary, carotid, and
cerebral lesions), benign tumors, a various types of cancers such
as primary tumors and tumor metastasis, abnormal stimulation of
endothelial cells (atherosclerosis), insults to body tissue due to
surgery, abnormal wound healing, abnormal angiogenesis, diseases
that produce fibrosis of tissue, repetitive motion disorders,
disorders of tissues that are not highly vascularized, and
proliferative responses associated with organ transplants.
[0056] Generally, cells in a benign tumor retain their
differentiated features and do not divide in a completely
uncontrolled manner. A benign tumor is usually localized and
nonmetastatic. Specific types benign tumors that can be treated
using the present invention include hemangiomas, hepatocellular
adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic
neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma,
fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas,
nodular regenerative hyperplasia, trachomas and pyogenic
granulomas.
[0057] In a melignant tumor cells become undifferentiated, do not
respond to the body's growth control signals, and multiply in an
uncontrolled manner. The malignant tumor is invasive and capable of
spreading to distant sites (metastasizing). Malignant tumors are
generally divided into two categories: primerary and secondary.
Primary tumors arise directly from the tissue in which they are
found. A secondary tumor, or metastasis, is a tumor which
originated elsewhere in the body but has now spread to a distant
organ. The common routes for metastasis are direct growth into
adjacent structures, spread through the vascular or lymphatic
systems, and tracking along tissue planes and body spaces
(peritoneal fluid, cerebrospinal fluid, etc.)
[0058] Specific types of cancers or malignant tumors, either
primary or secondary, that can be treated using this invention
include leukemia, breast cancer, skin cancer, bone cancer, prostate
cancer, liver cancer, lung cancer, brain cancer, cancer of the
larynx, gallbladder, pancreas, rectum, parathyroid, thyroid,
adrenal, neural tissue, head and neck, colon, stomach, bronchi,
kidneys, basal cell carcinoma, squamous cell carcinoma of both
ulcerating and papillary type, metastatic skin carcinoma, osteo
sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant
cell tumor, small-cell lung tumor, gallstones, islet cell tumor,
primary brain tumor, acute and chronic lymphocytic and granulocytic
tumors, hairy-cell tumor, adenoma, hyperplasia, medullary
carcinoma, pheochromocytoma, mucosal neuronms, intestinal
ganglloneuromas, hyperplastic corneal nerve tumor, marfanoid
habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater
tumor, cervical dysplasia and in situ carcinoma, neuroblastoma,
retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical
skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma,
osteogenic and other sarcoma, malignant hypercalcemia, renal cell
tumor, polycythermia Vera, adenocarcinoma, glioblastoma multiforma,
leukemias, lymphomas, malignant melanomas, epidermoid carcinomas,
and other carcinomas and sarcomas.
[0059] Treatment of abnormal cell proliferation due to insults to
body tissue during surgery may be possible for a variety of
surgical procedures, including joint surgery, bowel surgery, and
cheloid scarring. Diseases that produce fibrotic tissue include
emphysema. Repetitive motion disorders that may be treated using
the present invention include carpal tunnel syndrome. An example of
cell proliferative disorders that may be treated using the
invention is a bone tumor.
[0060] The proliferative responses associated with organ
transplantation that may be treated using this invention include
those proliferative responses contributing to potential organ
rejections or associated complications. Specifically, these
proliferative responses may occur during transplantation of the
heart, lung, liver, kidney, and other body organs or organ
systems.
[0061] Abnormal angiogenesis that may be may be treated using this
invention include those abnormal angiogenesis accompanying
rheumatoid arthritis, ischemic-reperfusion related brain edema and
injury, cortical ischemia, ovarian hyperplasia and
hypervascularity, (polycystic ovary syndrom), endometriosis,
psoriasis, diabetic retinopaphy, and other ocular angiogenic
diseases such as retinopathy of prematurity (retrolental
fibroplastic), macular degeneration, corneal graft rejection,
neuroscular glaucoma and Oster Webber syndrome.
[0062] Diseases associated with abnormal angiogenesis require or
induce vascular growth. For example, corneal angiogenesis involves
three phases: a pre-vascular latent period, active
neovascularization, and vascular maturation and regression. The
identity and mechanim of various angiogenic factors, including
elements of the inflammatory response, such as leukocytes,
platelets, cytokines, and eicosanoids, or unidentified plasma
constituents have yet to be revealed.
[0063] In another embodiment of the present invention, a method is
provided for treating diseases associated with undesired and
uncontrolled angiogenesis. The method comprises administering to a
patient suffering from uncontrolled angiogenesis a therapeutically
effective amount of CPT, such that formation of blood vessels is
inhibited. The particular dosage of CPT requires to inhibit
angiogenesis and/or angiogenic diseases may depend on the severity
of the condition, the route of administration, and related factors
that can be decided by the attending physician. Generally, accepted
and effective daily doses are the amount sufficient to effectively
inhibit angiogenesis and/or angiogenic diseases.
[0064] According to this embodiment, CPT may be used to treat a
variety of diseases associated with uncontrolled angiogenesis such
as retinal/choroidal neuvascularization and corneal
neovascularization. Examples of retinal/choroidal
neuvascularization include, but are not limited to, Bests diseases,
myopia, optic pits, Stargarts diseases, Pagets disease, vein
occlusion, artery occlusion, sickle cell anemia, sarcoid, syphilis,
pseudoxanthoma elasticum carotid abostructive diseases, chronic
uveitis/vitritis, mycobacterial infections, Lyme's disese, systemic
lupus erythematosis, retinopathy of prematurity, Eales disease,
diabetic retinopathy, macular degeneration, Bechets diseases,
infections causing a retinitis or chroiditis, presumed ocular
histoplasmosis, pars planitis, chronic retinal detachment,
hyperviscosity syndromes, toxoplasmosis, trauma and post-laser
complications, diseases associated with rubesis (neovascularization
of the angle) and diseases caused by the abnormal proliferation of
fibrovascular or fibrous tissue including all forms of
proliferative vitreoretinopathy. Examples of corneal
neuvascularization include, but are not limited to, epidemic
keratoconjunctivitis, Vitamin A deficiency, contact lens overwear,
atopic keratitis, superior limbic keratitis, pterygium keratitis
sicca, sjogrens, acne rosacea, phylectenulosis, diabetic
retinopathy, retinopathy of prematurity, corneal graft rejection,
Mooren ulcer, Terrien's marginal degeneration, marginal
keratolysis, polyarteritis, Wegener sarcoidosis, Scleritis,
periphigoid radial keratotomy, neovascular glaucoma and retrolental
fibroplasia, syphilis, Mycobacteria infections, lipid degeneration,
chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex
infections, Herpes zoster infections, protozoan infections and
Kaposi sarcoma.
[0065] In yet another embodiment of the present invention, a method
is provided for treating chronic inflammatory diseases associated
with uncontrolled angiogenesis. The method comprises administering
CPT to a patient suffering from a chronic inflammatory disease
associated with uncontrolled angiogenesis a therapeutically
effective amount of CPT, such that formation of blood vessels is
inhibited. The chronic inflammation depends on continuous formation
of capillary sprouts to maintain an influx of inflammatory cells.
The influx and presence of the inflammatory cells produce
granulomas and thus, maintains the chronic inflammatory state.
Inhibition of angiogenesis using CPT alone or in conjunction with
other anti-inflammatory agents may prevent the formation of the
granulosmas, thereby alleviating the disease. Examples of chronic
inflammatory disease include, but are not limited to, inflammatory
bowel diseases such as Crohn's disease and ulcerative colitis,
psoriasis, sarcoidois, and rhematoid arthritis.
[0066] Inflammatory bowel diseases such as Crohn's disease and
ulcerative colitis are characterized by chronic inflammation and
angiogenesis at various sites in the gastrointestinal tract. For
example, Crohn's disease occurs as a chronic transmural
inflammatory disease that most commonly affects the distal ileum
and colon but may also occur in any part of the gastrointestinal
tract from the mouth to the anus and perianal area. Patients with
Crohn's disease generally have chronic diarrhea associated with
abdominal pain, fever, anorexia, weight loss and abdominal
swelling. Ulcerative colitis is also a chronic, nonspecific,
inflammatory and ulcerative disease arising in the colonic mucosa
and is characterized by the presence of bloody diarrhea. These
inflammatory bowel diseases are generally caused by chronic
granulomatous inflammation throughout the gastrointestinal tract,
involving new capillary sprouts surrounded by a cylinder of
inflammatory cells. Inhibition of angiogenesis by CPT should
inhibit the formation of the sprouts and prevent the formation of
granulomas. The inflammatory bowel diseases also exhibit extra
intestinal manifectations, such as skin lesions. Such lesions are
characterized by inflammation and angiogenesis and can occur at
many sites other the gastrointestinal tract. Inhibition of
angiogenesis by CPT should reduce the influx of inflammatory cells
and prevent the lesion formation.
[0067] Sarcoidois, another chronic inflammatory disease, is
characterized as a multisystem granulomatous disorder. The
granulomas of this disease can form anywhere in the body and, thus,
the symtoms depend on the site of the granulomas and whether the
disease is active. The granulomas are created by the angiogenic
capillary sprouts providing a constant supply of inflammatory
cells. By using CPT to inhibit angionesis, such granulomas
formation can be inhibited. Psoriasis, also a chronic and recurrent
inflammatory disease, is characterized by papules and plaques of
various sizes. Treatment using CPT alone or in conjunction with
other anti-inflammatory agents should prevent the formation of new
blood vessels necessary to maintain the characteristic lesions and
provide the patient relief from the symptoms.
[0068] Rheumatoid arthritis (RA) is also a chronic inflammatory
disease characterized by non-specific inflammation of the
peripheral joints. It is believed that the blood vessels in the
synovial lining of the joints undergo angiogenesis. In addition to
forming new vascular networks, the endothelial cells release
factors and reactive oxygen species that lead to pannus growth and
cartilage destruction. The factors involved in angiogenesis may
actively contribute to, and help maintain, the chronically inflamed
state of rheumatoid arthritis. Treatment using CPT alone or in
conjunction with other anti-RA agents should prevent the formation
of new blood vessels necessary to maintain the chronic inflammation
and provide the RA patient relief from the symptoms.
[0069] CPT may also be used in conjunction with other
anti-angiogenesis agents to inhibit undesirable and uncontrolled
angiogenesis. Examples of anti-angiogenesis agents include, but are
not limited to, retinoid acid and derivatives thereof,
2-methoxyestradiol, ANGIOSTATIN.TM. protein, ENDOSTATIN.TM.
protein, suramin, squalamine, tissue inhibitor of
metalloproteinase-I, tissue inhibitor of metalloproteinase-2,
plasminogen activator inhibitor-1, plasminogen activator
inhibitor-2, cartilage-derived inhibitor, paclitaxel, platelet
factor 4, protamine sulphate (clupeine), sulphated chitin
derivatives (prepared from queen crab shells), sulphated
polysaccharide peptidoglycan complex (sp-pg), staurosporine,
modulators of matrix metabolism, including for example, proline
analogs ((I-azetidine-2-carboxylic acid (LACA), cishydroxyproline,
d,l-3,4-dehydroproline, thiaproline], .alpha.,.alpha.-dipyridyl,
.beta.-aminopropionitrile fumarate,
4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate,
mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3,
chymostatin, beta.-cyclodextrin tetradecasulfate, eponemycin;
fumagillin, gold sodium thiomalate, d-penicillamine (CDPT),
beta.-1-anticollagenase-serum, alpha.2-antiplasmin, bisantrene,
lobenzarit disodium, n-(2carboxyphenyl-4-chloroanthronilic acid
disodium or "CCA", thalidomide; angostatic steroid,
cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94.
Other anti-angiogenesis agents include antibodies, preferably
monoclonal antibodies against these angiogenic growth factors:
bFGF, aFGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2.
Ferrara N. and Alitalo, K. "Clinical application of angiogenic
growth factors and their inhibitors" (1999) Nature Medicine
5:1359-1364.
4. Compositions, Formulations, and Kits
[0070] Compositions according to the present invention might
include a CPT, a non-CPT therapeutic agent, together with a
pharmaceutical excipient. The composition preferably have a
therapeutic synergy in the treatment of a disease, or a synergistic
effect on the subjected being treated. As used herein, a
synergistic effect is achieved when a greater therapeutic effect
results with a combination therapy than using either drug or
monotherapy alone. One advantage of combination therapy with a
synergistic effect is that lower dosages of one or both of the
drugs or therapies may be used so that the therapeutic index is
increased and toxic side effects are reduced.
[0071] In an aspect, the invention is directed to kits for treating
diseases associated with abnormal cell proliferation. In one
embodiment, the kit comprises a container that contains a compound
selected from the group consisting of 20(S)-camptothecin, analog of
20(S)-camptothecin, derivative of 20(S)-camptothecin, prodrug of
20(S)-camptothecin, and pharmaceutically active metabolite of 20(S)
-camptothecin; and one or more agents selected from the group
conisting of alkylating agent, antibiotic agent, antimetabolic
agent, hormonal agent, plant-derived agent, anti-angiogenesis agent
and biologic agent.
[0072] According to this embodiment, the 20(S)-camptothecin may be
9-nitrocamptothecin, or 9-aminocamptothecin. Also according this
embodiment, the biological agent may an immuno-modulating protein,
monoclonal antibody against tumor antigen, tumor suppressor gene,
or cancer vaccine. Other examples of the 20(S)-camptothecin,
analogs of 20(S)-camptothecin, derivatives of 20(S)-camptothecin,
prodrugs of 20(S)-camptothecin, and pharmaceutically active
metabolites of 20(S) -camptothecin are listed in Section 1. Other
examples of the alkylating agent, antibiotic agent, antimetabolic
agent, hormonal agent, plant-derived agent, anti-angiogenesis agent
and biologic agent are listed in Section 2.
5. Delivery of Therapeutic Agents
[0073] A wide variety of delivery methods and formulations for
different delivery methods are intended to be encompassed by the
combination therapies of the present invention.
[0074] The inventive combination of therapeutic agents may be
administered as compositions that comprise the inventive
combination of therapeutic agents. Such compositions may include,
in addition to the inventive combination of therapeutic agents,
conventional pharmaceutical excipients, and other conventional,
pharmaceutically inactive agents. Additionally, the compositions
may include active agents in addition to the inventive combination
of therapeutic agents. These additional active agents may include
additional compounds according to the invention, or one or more
other pharmaceutically active agents. In preferable embodiments,
the inventive compositions will contain the active agents,
including the inventive combination of therapeutic agents, in an
amount effective to treat an indication of interest.
[0075] The inventive combination of therapeutic agents and/or
compositions may be administered or coadministered orally,
parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually, intramuscularly, rectally,
transbuccally, intranasally, liposomally, via inhalation,
vaginally, intraoccularly, via local delivery (for example by
catheter or stent), subcutaneously, intraadiposally,
intraarticularly, or intrathecally. The compounds and/or
compositions according to the invention may also be administered or
coadministered in slow release dosage forms.
[0076] The inventive combination of therapeutic agents and
compositions may be administered by a variety of routes, and may be
administered or coadministered in any conventional dosage form.
Coadministration in the context of this invention is defined to
mean the administration of more than one therapeutic in the course
of a coordinated treatment to achieve an improved clinical outcome.
Such coadministration may also be coextensive, that is, occurring
during overlapping periods of time.
[0077] One therapeutically interesting route of administration or
coadministration is local delivery. Local delivery of inhibitory
amounts of inventive combination of therapeutic agents and/or
compositions can be by a variety of techniques and structures that
administer the inventive combination of therapeutic agents and/or
compositions at or near a desired site. Examples of local delivery
techniques and structures are not intended to be limiting but
rather as illustrative of the techniques and structures available.
Examples include local delivery catheters, site specific carriers,
implants, direct injection, or direct applications.
[0078] Local delivery by a catheter allows the administration of a
inventive combination of therapeutic agents and/or compositions
directly to the desired site. Examples of local delivery using a
balloon catheter are described in EP 383 492 A2 and U.S. Pat. No.
4,636,195 to Wolinsky. Additional examples of local, catheter-based
techniques and structures are disclosed in U.S. Pat. No. 5,049,132
to Shaffer et al. and U.S. Pat No. 5,286,254 to Shapland et al.
[0079] Generally, the catheter must be placed such that the
inventive combination of therapeutic agents s and/or compositions
can be delivered at or near the desired site. Dosages delivered
through the catheter can vary, according to determinations made by
one of skill, but often are in amounts effective to create a
cytotoxic or cytostatic effect at the desired site. Preferably,
these total amounts are less than the total amounts for systemic
administration of the inventive combination of therapeutic agents
and/or compositions, and are less than the maximum tolerated dose.
The inventive combination of therapeutic agents s and/or
compositions delivered through catheters preferably should be
formulated to a viscosity that enables delivery through a small
treatment catheter, and may be formulated with pharmaceutically
acceptable additional ingredients (active and inactive).
[0080] Local delivery by an implant describes the placement of a
matrix that contains the inventive combination of therapeutic
agents s and/or compositions into the desired site. The implant may
be deposited by surgery or other means. The implanted matrix
releases the inventive combination of therapeutic agents s and/or
compositions by diffusion, chemical reaction, solvent activators,
or other equivalent mechanisms. Examples are set forth in Lange,
Science 249:1527-1533 (September, 1990). Often the implants may be
in a form that releases the inventive combination of therapeutic
agents s and/or compositions over time; these implants are termed
time-release implants. The material of construction for the
implants will vary according to the nature of the implant and the
specific use to which it will be put. For example, biostable
implants may have a rigid or semi-rigid support structure, with
inventive combination of therapeutic agents and/or composition
delivery taking place through a coating or a porous support
structure. Other implants made be made of a liquid that stiffens
after being implanted or may be made of a gel. The amounts of
inventive combination of therapeutic agents and/or composition
present in or on the implant may be in an amount effective to treat
cell proliferation generally, or a specific proliferation
indication, such as the indications discussed herein.
[0081] One example of local delivery of the inventive combination
of therapeutic agents and/or composition by an implant is use of a
biostable or bioabsorbable plug or patch or similar geometry that
can deliver the inventive combination of therapeutic agents and/or
composition once placed in or near the desired site. An example of
such implants can be found in U.S. Pat. No. 5,429,634 to Narciso,
Jr.
[0082] A particular application of use of an implant according to
the invention is treatment of cell proliferation in tissue that is
not highly vascularized, as discussed briefly above. An example of
such tissue is bone tissue. The difficulty in treating uncontrolled
proliferative cell growth in bone tissue may be exemplified by the
difficulties in treating bone tumors. Such tumors are typically
refractory to treatment, in part because bone tissue is not highly
vascularized. An implant in or near the proliferative site may
potentially have localized cytotoxic or cytostatic effects with
regard to the proliferative site. Therefore, in one embodiment, the
invention may be used to treat bone tumors.
[0083] Another example of local delivery by an implant is the use
of a stent. Stents are designed to mechanically prevent the
collapse and reocclusion of the coronary arteries. Incorporating an
inventive combination of therapeutic agents and/or composition into
the stent may deliver the agent directly to or near the
proliferative site. Certain aspects of local delivery by such
techniques and structures are described in Kohn, Pharmaceutical
Technology (October, 1990). Stents may be coated with the inventive
combination of therapeutic agents and/or composition to be
delivered. Examples of such techniques and structures may be found
in U.S. Pat. No. 5,464,650 to Berg et al., U.S. Pat. No. 5,545,208
to Wolff et al., U.S. Pat. No. 5,649,977 to Campbell, U.S. Pat. No.
5,679,400 to Tuch, EP 0 716 836 to Tartaglia et al. Alternatively,
the inventive combination of therapeutic agents and/or composition
loaded stent may be biorotable, i.e. designed to dissolve, thus
releasing the inventive combination of therapeutic agents and/or
composition in or near the desired site, as disclosed in U.S. Pat.
No. 5,527,337 to Stack et al. The present invention can be used
with a wide variety of stent configurations, including, but not
limited to shape memory alloy stents, expandable stents, and stents
formed in situ.
[0084] Amounts of the inventive combination of therapeutic agents
and/or composition delivered by the stent can vary, according to
determinations made by one of skill, but preferably are in amounts
effective to create a cytotoxic or cytostatic effect at the desired
site. Preferably, these total amounts are less than the total
amounts for systemic administration of the inventive combination of
therapeutic agents and/or composition, and are preferably less than
the maximum tolerated dose. Appropriate release times can vary, but
preferably should last from about 1 hour to about 6 months, most
preferably from about 1 week to about 4 weeks. Formulations
including the inventive combination of therapeutic agents and/or
composition for delivery of the agent via the stent can vary, as
determinable by one of skill, according to the particular
situation, and as generally taught herein.
[0085] Another example is a delivery system in which a polymer that
contains the inventive combination of therapeutic agents and/or
composition is injected into the target cells in liquid form. The
polymer then cures to form the implant in situ. One variation of
this technique and structure is described in WO 90/03768 to
Donn.
[0086] Another example is the delivery of the inventive combination
of therapeutic agents and/or composition by polymeric endoluminal
sealing. This technique and structure uses a catheter to apply a
polymeric implant to the interior surface of the lumen. The
inventive combination of therapeutic agents and/or composition
incorporated into the biodegradable polymer implant is thereby
released at the desired site. One example of this technique and
structure is described in WO 90/01969 to Schindler.
[0087] Another example of local delivery by an implant is by direct
injection of vesicles or microparticulates into the desired site.
These microparticulates may comprise substances such as proteins,
lipids, carbohydrates or synthetic polymers. These
microparticulates have the inventive combination of therapeutic
agents and/or composition incorporated throughout the microparticle
or over the microparticle as a coating. Examples of delivery
systems incorporating microparticulates are described in Lange,
Science, 249:1527-1533 (September, 1990) and Mathiowitz, et al., J.
App. Poly Sci. 26:809 (1981).
[0088] Local delivery by site specific carriers describes attaching
the inventive combination of therapeutic agents and/or composition
to a carrier which will direct the drug to the desired site.
Examples of this delivery technique and structure include the use
of carriers such as a protein ligand or a monoclonal antibody.
Certain aspects of these techniques and structures are described in
Lange, Science 249:1527-1533.
[0089] Local delivery also includes the use of topical
applications. An example of a local delivery by topical application
is applying the inventive combination of therapeutic agents and/or
composition directly to an arterial bypass graft during a surgical
procedure. Other equivalent examples will no doubt occur to one of
skill in the art.
[0090] The inventive combination of therapeutic agents s and/or
compositions may be used in the form of kits. The arrangement and
construction of such kits is conventionally known to one of skill
in the art. Such kits may include containers for containing the
inventive combination of therapeutic agents s and/or compositions,
and/or other apparatus for administering the inventive combination
of therapeutic agents and/or compositions.
[0091] It will be apparent to those skilled in the art that various
modifications and variations can be made in the compounds,
compositions, kits, and methods of the present invention without
departing from the spirit or scope of the invention. Thus, it is
intended that the present invention cover the modifications and
variations of this invention provided they come within the scope of
the appended claims and their equivalents.
* * * * *