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 14C-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 C6 glioma cells in vitro than the cisplatin-methionine complex. Exposure of C6 glioma cells to cisplatin-methionine, however, resulted in a 50%-60% reduction in 3H-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.


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