Resistance to chemotherapy is a major stumbling block in the treatment of cancer. Recently, a role has been defined for the overexpression of the oncogene bcl-2 in the production of resistance to chemotherapeutic-induced apoptosis in some tumors, including advanced breast cancer, acute myeloid leukemia, prostate cancer, and neural crest tumors such as neuroblastoma. It is therefore critical that new chemotherapeutic strategies be developed to overcome chemoresistance in tumors that overexpress bcl-2. Previous reports have documented that overexpression of bcl-2 is accompanied by an increase in the intracellular concentration of reduced glutathione (GSH). One possible way to overcome chemoresistance in bcl-2 overexpressing cells would therefore be to use chemotherapeutic drugs whose activity is enhanced by reaction with GSH. The applicant has performed extensive studies of one such group of agents, the enediynes. The enediynes are prodrugs that require reductive activation by thiols for their antineoplastic activity. As such, their activity both in vitro and in vivo is directly proportional to the cellular concentration of thiols, including GSH. The applicant has recently shown that, unlike other chemotherapeutic drugs, the enediyne neocarzinostatin (NCS) is a more potent inducer of apoptosis in tumor cells that overexpress bcl-2 than in those that do not. She proposes now to determine the mechanisms for both the increase in GSH concentration and the increase in sensitivity to enediyne-induced apoptosis in bcl-2-overexpressing cells. She will then use her understanding of these phenomena and their mechanisms to design, implement, and optimize a chemotherapeutic strategy that exploits the unique molecular and biochemical characteristics bcl-2-overexpressing tumor cells to target them for drug-induced apoptosis. This approach has the benefit of maximizing efficacy in bcl-2-overexpressing tumor cells, minimizing toxicity to normal cells, and identifying those tumors for which this is likely to be an effective regimen. Furthermore, it will establish in a preclinical model the potential of this novel strategy for treatment of patients for whom there is otherwise no reasonable chance of survival.
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