POLYAMINES AS A POTENTIAL CHEMOTHERAPEUTIC TARGET

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The overall objective of this Program is to utilize available polyamine inhibitors and analogs to study polyamine biosynthesis, metabolism and function as it occurs in neoplastic cell types and, at the same time, to identify and evaluate unique target sites for potential chemotherapeutic intervention. The recent availability of novel polyamine analogs and inhibitors and novel biological systems within this Program has afforded new opportunities to study various aspects of polyamine biology. Included among these is the use of a newly characterized inhibitor of S- adenosylmethionine decarboxylase to deplete or selectively modulate and control all three intracellular polyamine pools. These new leads will be used to: (1) characterized the individual polyamine requirement for cell growth and differentiation; (2) study the relationship between individual polyamine pools and regulation of the polyamine transport system and certain biosynthetic enzymes; (3) examine the significance of the by-product of polyamine biosynthesis, 5'-deoxy-5'- methylthioadenosine, to cell growth and differentiation; (4) study polyamine-DNA interactions in the context of intact cells; (5) examine the role of oncogene expression as a determinant of sensitivity to polyamine analogs and inhibitors and (f) evaluate the potential of specific enzymes and mechanisms as chemotherapeutic targets. Although diverse, the proposed research is unified under the common goal of this Program and, in nearly all cases, feasibility is supported by progress and/or preliminary data.