THE NEPHROTOXICITY, CYTOTOXICITY AND RENAL HANDLING OF A CISPLATIN-METHIONINE COMPLEX IN MALE WISTAR RATS

When cisplatin is administered in the form of a cisplatin-methionine substitution complex, high doses of cisplatin can be tolerated with no obvious signs of renal toxicity. We have demonstrated that male Wistar rats receiving a single i.p. dose of cisplatin-methionine at a 1:5 ratio (by weight) did not exhibit cisplatin-induced nephrotoxicity, while cisplatin administered alone at an identical concentration (6 mg/kg) resulted in marked renal toxicity in all animals treated. Using renal cortical slices prepared from untreated rats, we demonstrated that cisplatin, but not cisplatin-methionine, inhibited the accumulation. of C-14-tetraethylammonium (TEA). This observation suggests that cisplatin, unlike cisplatin-methionine, is a substrate for the organic base transport system. In addition, cisplatin alone was more cytotoxic to C-6 glioma cells in vitro than the cisplatin-methionine complex. Exposure of C-6 glioma cells to cisplatin-methionine, however, resulted in a 50%-60% reduction in H-3-thymidine incorporation at cisplatin:methionine ratios up to 1:10. These results indicate that cisplatin-methionine is significantly cytotoxic yet lacks cisplatin-associated renal toxicity and may, therefore, have a role in the treatment of human malignancies.