The study outlined in this grant proposal will focus on a group of selected tetravalent platinum-based antitumor drugs. The present proposal will permit us to gain understanding of 1,2-diaminocyclohexane platinum(IV) complexes which may have actions via mechanisms other than simple reduction to their analogous 1,2-diaminocyclohexane platinum(II) complexes. Such an undertaking will involve broad aspects of biochemical, cellular and in vivo evaluation of drug pharmacology which we believe to be essential in the eventual selection of clinical drug candidates. Specifically, a series of isomeric (i.e. trans-R,R, trans- S,S and cis) 1,2-diaminocyclohexane platinum(IV) complexes with selected and specifically chosen axial and equatorial leaving ligands will be synthesized, the nature and kinetics of in vitro and in vivo transformation products of these tetravalent platinum complexes examined, the antitumor activity in vitro and in vivo against murine (e.g. L1210/0, L1210/cisplatin) and human (Brown melanoma) tumor lines determined, and potential to produce specific target organ toxicities evaluated. We believe the proposed studies will lead to a valuable understanding of the efficacy, toxicity, cellular and biochemical pharmacology of platinum(IV) complexes. The information will be essential in evaluating these complexes as a distinct class of platinum antitumor agents and in the design and development of a highly useful third-generation platinum(IV) antitumor drug.
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