Three independent research programs with complementary skills and expertise will interact in a concerted effort to identify and therapeutically develop new polyamine analogs as potential anticancer agents. The proposed target of these analogs is interference with various polyamine homeostatic responses as a means to achieve polyamine depletion. This approach is supported by several recent findings with the lead compound, N1,N11-bis- (ethyl)norspermine, suggesting a causal relationship between an unusual polyamine enzyme response (i.e. massive induction of spermidine/spermine N1-acetyltransferase activity) and potent antitumor activity against human melanoma xenografts. As proposed, the Program includes the medicinal chemistry project of Dr. Bergeron (University of Florida, Gainesville) with primary responsibility for new analog synthesis, the biochemical pharmacology project of Dr. Carl Porter (P.I., Roswell Park Cancer Institute, Buffalo, NY) with primary responsibility for in vitro/in vivo mechanism of analog action studies and the experimental therapeutics project of Dr. Ralph Bernacki (Roswell Park Cancer Institute) with primary responsibility for therapeutic evaluation and development. Within this interactive framework, there exist two broad scientific themes, (a) drug discovery focussing on the synthesis and biological evaluation of new polyamine analogs and (b) drug development focussing on the study and partial therapeutic development of promising compounds including the lead analog. It is the overall goal of this Program to produce a polyamine analog with a defined mechanism of action and sufficient antitumor activity to potentially prove useful in the treatment of certain human malignancies.
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