Nephrotoxicity in patients on long-term platinum (II) chemotherapy constitutes a limit both in dosage and duration of chemotherapy; successful use of adjuvant platinum chemotherapy requires a solution to this problem. The principal investigator has recently demonstrated the success of a dithiocarbamate rescue procedure to inhibit nephrotoxicity in an animal model. The research proposed herein is designed: (1) to provide information about the interaction of dithiocarbamate with membrane-bound platinum and platinum DNA complexes and hence increase our knowledge of the mechanism of platinum toxicity; (2) to confirm that cis-platinum, when given in combination with dithiocarbamate, is still effective as an anti-tumor agent; (3) to demonstrate that oral disulfiram is an effective rescue agent for platinum toxicity. The interaction of dithiocarbamate and preformed complexes of platinum with renal tubular membranes and with DNA will be evaluated spectrophotometrically to determine whether dithiocarbamate can remove platinum from these complexes. Administration of cis-platinum and dithiocarbamate will be carried out in tumor-bearing animals and the effect of the drug combination on tumor size compared with that of platinum alone. The pharmacokinetics of oral disulfiram in the rabbit will be explored as a model for this drug as a rescue agent in a clinical setting.
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