It is universally acknowledged that the major problem in the management of AML is the high probability of disease recurrence. This reflects the very low likelihood of successful treatment outcome once recurrence occurs. In fact, almost invariably, outcome following application of the same treatment regimen is worst at relapse than at initial diagnosis. Reasons for the this fundamental clinical observation remain obscure. As a corollary, a major difficulty with development of new salvage therapies has been lack of understanding of the cellular targets toward which such therapies should be directed. However, in the last few years, the critical role of apoptosis in determining response to chemotherapy has been established; furthermore, some apoptotic pathways have been unraveled. These developments make it possible to design drugs targeting these pathways and thus, to demonstrate the feasibility of this approach. Knowledge of pathways involved in death of AML cells may also improve our ability to predict outcome in the regulation of cell death pathways are being studied in Projects 1-3. They include Bcl-2 and IAP family members. The Core will conduct the clinical trials designed to assess whether the ability of drugs such as antisense to bcl-2, bryostatin UCN01 and Dolastatin to modulate mediators of apoptosis parallels the clinical response to these drugs.
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