The goal of the proposed research is to examine the use of dithiocarbamate chelating agents (which we have recently prepared) in controlling the nephrotoxicity of cis-platinum at normal and elevated dosage levels. Renal function in experimental animals (rats) will be monitored (via measurement of serum creatinine levels and blood urea nitrogen values) as the animals are taken through various protocols designed to allow the administration of cis-platinum under conditions selected to produce minimum nephrotoxicity. These same protocols will be examined for anti-tumor efficacy in the rat using cis-platinum sensitive Walker 256 carcinosarcoma (ATCC)(CL38) to determine the effect of the measures used to reduce nephrotoxicity on the anti-cancer activity of the cis-platinum. Analogous studies will be carried out using other transplantable tumors in rats and mice (70). Dose-response curves will be developed to determine the effect of chelating agent dosage on the course of blood urea nitrogen levels, serum creatine values and platinum mobilization. The chelating agents which we plan to use are primarily ones which we have prepared and shown to be capable of reducing the nephrotoxicity of cis-platinum without altering the anti-cancer activity significantly, in the Walker 256 model system, though structurally related compounds will also be examined. Experimental determination of the effect of these chelating agents on the cytotoxicity of cis-platinum will also be carried out as preliminary results indicate that perhaps only part of the reduction in nephrotoxicity which has been observed is due to chelation.
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