The studies outlined in this grant proposal are focused on a group of specific platinum-based antitumor drugs that already show great promise as active and relatively nontoxic oncolytic chemotherapeutic agents. We have discovered that specific isomers of diaminocyclohexane-platinum drugs appear to possess superior antitumor activity over that of chylohexane-platinum drugs apprear to possess superior antitumor activity over that of their respective parental racemic mixtures. This proposal will permit the chemical syntheses of individual drug isomers as well as limited preclinical evaluation of each compound's therapeutic efficacy and toxicology. Specifically, a targeted series of """"""""third generation"""""""" platinum drugs will be synthesized (as well as their individual cis- trans-d, and trans-1 isomers), evaluated in vitro and in vivo for therapeutic efficacy against L1210 and an L1210 cell line resistant to Platinol, and further evaluated for their potential to produce nephrotoxicity. Additional integrated studies will utilize active and inactive isomeric platinum compounds to probe the correlation of an agent's antitumor efficacy with specific drug-mediated membrane (ferricyanide reductase, methionine transport), cytosolic (cAMP concentration) and DNA (nuclear histone phosphorylation and platinum-DNA adduct identification) """"""""targets"""""""". We believe the proposed studies will lead to a valuable understanding of the contribution of individual platinum isomers to the overall biochemical pharmacology, antitumor efficacy and toxicity (i.e. therapeutic index) of a parental racemic DACH-platinum drug. Furthermore, as the preliminary data demonstrate, it is clearly evident that the further development of the trans-R,R isomeric derivatives will, in all probability, lead to the development of a highly useful platinum antitumor drug.
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