Resistance to chemotherapy severely limits the success of treatment for cancer. It has been increasingly recognized that many cancers are globally resistant to chemotherapeutic agents because of their overexpression of Bcl-2 or related antiapoptotic proteins. In the past three years, funded by our present R01, we have begun to develop a chemotherapeutic approach that takes advantage of the enhanced capacity for glutathione turnover seen in cells that overexpress Bcl-2. Using chemotherapeutic agents that require reductive activation by glutathione, we have demonstrated potentiation, rather than abrogation of apoptosis in cancer cells that overexpress Bcl-2. Our recent studies suggest that potentiation by Bcl-2 of apoptosis induced by reduction-dependent chemotherapeutic agents is not universal, but rather, requires both that Bcl-2 alter glutathione turnover and the cells express caspase 3. The present proposal is aimed at determining the mechanistic relationship between Bcl-2-mediated enhancement of glutathione turnover and cleavage of Bcl-2 by caspase 3. In addition, it is aimed at the development of a panel of predictive tests to identify those Bcl-2-overexpressing tumors that will demonstrate potentiation of apoptosis in response to reduction-dependent chemotherapeutic agent treatment. Ultimately, this predictive panel will help to identify those patients whose chemoresistant tumors are likely to be particularly sensitive to enediyne treatment. ? ?
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