Restoring cancer-suppressing functions to neoplastic cells through DNA hypomethylation

Abstract

Compositions and methods are provided for treating diseases associated with abnormal cell proliferation such as cancer by storing inherent tumor-suppressing functions of neoplastic cells through DNA hypomethylation. The method comprises: delivering to a patient suffering from cancer a therapeutically effective amount of a DNA methylation inhibitor such as decitabine, in combination with an effective amount of an anti-neoplastic agent whose activity as an anti-neoplastic agent in vivo is adversely affected by aberrant DNA methylation. The anti-neoplastic agent can be an alkylating agent such as a platinum compound, an antibiotic agent, an antimetabolic agent, a retinoid, a hormonal agent, a plant-derived agent, an anti-angiogenesis agent and a biologic agent.

What is claimed is:  
     
         1 . A method for treating a disease associated with abnormal cell proliferation or abnormal angiogenesis, comprising: 
 administering to a patient having the disease a DNA methylation inhibitor at a dose of 1-100 mg/m 2  per day in combination with a therapeutically effective amount of a platinum compound.    
     
     
         2 . The method according to  claim 1 , wherein the DNA methylation inhibitor is a cytidine analog.  
     
     
         3 . The method according to  claim 2 , wherein the cytidine analog is decitabine.  
     
     
         4 . The method according to  claim 1 , wherein the disease associated with the abnormal cell proliferation is selected from the group consisting of restenosis, benign tumor, cancer, hematological disorder and atherosclerosis.  
     
     
         5 . The method according to  claim 4 , 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.  
     
     
         6 . The method according to  claim 4 , wherein the cancer is selected from the group consisting of 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, 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, malignant melanomas, and epidermoid carcinomas.  
     
     
         7 . The method according to  claim 4 , wherein the cancer is ovarian cancer.  
     
     
         8 . The method according to  claim 4 , wherein the patient has cancer that is resistant to the treatment of the platinum compound.  
     
     
         9 . The method according to  claim 4 , wherein the patient has ovarian cancer that is resistant to the treatment of the platinum compound.  
     
     
         10 . The method according to  claim 4 , wherein the hematological disorder is selected from acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphoblastic leukemia, Hodgkin's disease, Non-Hodgkin's Lymphomas, myelodysplastic syndromes, and sickle cell anemia.  
     
     
         11 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and the platinum compound is carboplatin.  
     
     
         12 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and the platinum compound is cisplatin.  
     
     
         13 . The method of  claim 1 , wherein the DNA methylation inhibitor is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, or intrathecally.  
     
     
         14 . The method of  claim 1 , wherein the DNA methylation inhibitor is administered subcutaneously or intravenously.  
     
     
         15 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and is administered intravenously or subcutaneously.  
     
     
         16 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and administered to the patient at a dose of 2-50 mg/m 2  per day.  
     
     
         17 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and administered to the patient at a dose of 5-20 mg/m 2  per day.  
     
     
         18 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and administered to the patient intravenously at a dose of 1-100 mg/m 2  per day.  
     
     
         19 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and administered to the patient prior to administering the platinum compound to the patient.  
     
     
         20 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and administered to the patient after the administering the platinum compound to the patient.