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.

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 α, interferon β, interferon γ, 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® (Trastruzumab), or RITUXAN® (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, α-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, α, α-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, D-penicillamine, β-1-anticollagenase-serum, α-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.