Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-20
2002-07-16
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S142100
Reexamination Certificate
active
06420378
ABSTRACT:
FIELD OF THE INVENTION
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
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
20
H
16
N
2
O
4
.
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+. 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 type treatment of advanced gastrointestinal cancer
, Cancer Chemother Rep. 56:95-101 (1972).
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.
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.
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)-Camptothecin (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 xenogcrafts
, Science 246:1046-1048 (1989).
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).
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.
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.
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
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.
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.
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).
Examples of antibiotic agents include, but are not limited to, anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione), mitomycin C, bleomycin, dactinomycin, plicatomycin.
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.
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.
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).
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.
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 &agr;, interferon &bgr; (fibroblast interferon) and interferon &ggr; (fibroblast interferon). Examples of such cytokines include, but are not limited to erythropoietin (epoietin &agr;), granulocyte-CSF (filgrast
Goldberg Jerome D.
SuperGen, Inc.
Weitz David J.
Wilson Sonsini Goodrich & Rosati
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