Various polyamine derivatives and inhibitors are proposed for evaluation as antiproliferative agents and for use in assessing the potential of polyamine biosynthesis and/or function in cancer chemotherapy. Two experimental antiproliferative strategies are detailed - one relying on increased uptake of polyamines by rapidly proliferating tissues and the other on elevated polyamine biosynthetic activity by such tissues. In the first, spermidine (Spd) with biologically-active moieties affixed at the N4 position will serve to facilitate their delivery to the interior of tumor cells and ultimately to nucleic acids. N4-Spd derivatives including those to be used as probes for further characterization of the cellular uptake mechanism will be synthesized. In the second strategy, N1,N8 akyl derivatives of Spd will serve as potent regulators of polyamine biosynthesis. N1,N8 bis(ethyl)Spd will be used as the model compound for evaluating the usefulness of the strategy and for elucidating the mechanisms involved. Murine L1210 leukemia cells grown in vitro and in vivo will be used to study parameters related to growth inhibition, Spd uptake, polyamine and S-adenosylmethionine metabolism, DNA, RNA and protein biosynthesis and regulatory mechanisms. In addition, aspects of polyamine biology and metabolism which bear directly on the above strategies are proposed for study. These include localization of intracellular Spd (or derivatives), and structure activity analyses with amine oxidase systems and polyamine-mediated changes in DNA structure and integrity. While the primary goal of this proposal is to identify new and useful anticancer agents and strategies, it is anticipated that information will be generated that is relevant to the role of polyamines in cell proliferation and hence to our understanding of neoplastic processes.
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