Ormaplatin [tetrachloro(d,1-trans) 1,2-diaminocyclohexaneplatinum(IV)] (also known as tetraplatin) is a second generation platinum drug that has recently entered phase I clinical trials. We have characterized the biotransformation of ormaplatin in tissue culture medium, in L1210 cells, and in rat plasma (both in vitro and in vivo). We have also shown that both diethyldithiocarbonate (DDTC) and S-2(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) are effective at reducing ormaplatin toxicity in the Fischer-344 rat and have characterized the effects of DDTC on the plasma biotransformations or ormaplatin. We now propose the following: (1) We plan to determine the and therapeutic effectiveness of the major plasma biotransformation products. These data should allow one to optimize the therapeutic potential of ormaplatin by selecting protocols that maximize the therapeutically effective biotransformation products and minimize the toxic ones. (2) We plan to characterize the intracellular biotransformations of ormaplatin in various tissues (liver, kidney, spleen and intestine) of the rat. These studies should allow a better understanding of the tissue selective toxicity of ormaplatin and other platinum drugs. (3) We plan to determine the effects of DDTC and WR-2721 on the intracellular tissue biotransformations of ormaplatin. In the case of DDTC we also plan to quantitate its effectiveness at removing Pt-protein adducts and quenching PtDNA monoadducts in the same tissues. (4) We also plan to determine the effect of i.v. sodium thiosulfate on the toxicity of i.p. ormaplatin in the Fischer-344 rat and determine the effect of thiosulfate on the peritoneal, plasma and tissue biotranformations of ormaplatin under the same treatment conditions. These studies should improve our understanding of how these compounds reduce the toxicity of ormaplatin and related compounds such as cisplatin. These data might also allow the selection and/or design of modifiers which have improved selectivity for reducing the toxic side effects of platinum drugs without intefering with their therapeutic usefulness.
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