The objective of this project is to develop a new drug from a proprietary class of novel pyrimidine cyclic disulfides for the treatment of breast cancer. The prototype member of this class, 3H-I,2-Dithiolo[4,3-d] pyrimidin-5,7 dione (M-47), was shown to have confirmed growth inhibitory activity against several human tumors including the multi-drug resistant human breast cancer cell line MDA435/LCC6 (IC50 = 1-2-microM). We have also shown that M-47 damages DNA in cells at doses it inhibits cell growth. The principal goal in Phase I is to determine the efficacy of M-47 in a nude/athymic mouse model of multi-drug resistant human breast cancer. An additional goal of Phase I is to study the mechanism of DNA damage produced by M-47, which requires preparation of the S-oxide derivative for comparison, by alkaline elution analysis. In Phase II a small number of structural analogs of M-47 will be synthesized and investigated in an effort to enhance potency and decrease toxicity. Once an optimal compound is determined, pharmaceutical development, safety and efficacy studies will be conducted to support filing of an IND application with the FDA. PROPOSED COMMERCIAL APPLICATION: Breast cancer is the most common form of malignant disease among women, and is the number one cause of death of women between the ages of 40-45. The National Cancer Institute estimates that the overall cost for all types of cancer is $104 billion. The treatment of breast, lung and prostate cancer account for over half of the cost. Chemotherapy is the treatment of choice for estrogen receptor negative metastatic breast cancer. Therefore an obvious opportunity exists in this large, un-met marketplace.
Public Health Relevance: This Public Health Relevance is not available.
Thesaurus Terms: Antineoplastic, Breast Neoplasm, Drug Design /Synthesis /Production, Drug Screening /Evaluation, Neoplasm /Cancer Chemotherapy, Nonhuman Therapy Evaluation, Pyrimidine Dna Damage, Chemical Synthesis, Cytotoxicity, Disulfide Bond, Multidrug Resistance Athymic Mouse, Disease Model, Female, High Performance Liquid Chromatography
