Effects of fosfomycin, mesna, and sodium thiosulfate on the toxicity and antitumor activity of cisplatin.

Abstract

Fosfomycin and mesna were investigated in rats and mice concerning their detoxifying effects on cisplatin toxicity in comparison to sodium thiosulfate, a known protector against cisplatin nephrotoxicity. After separate i.p. injection of cisplatin and fosfomycin (500 mg/kg) or mesna (800 mg/kg) a slight increase in the 50% lethal dose of cisplatin was found in all animals. In mice sodium thiosulfate proved to be far more effective in preventing lethal toxicity and nephrotoxicity as measured by blood urea nitrogen increase. Fosfomycin and mesna were almost without influence on cisplatin treatment of L-1210 leukemia whereas their inhibition of the antitumor effect against S-180 ascites sarcoma (increase of in cisplatin dose to cure 50% of animals from 2.0 mg/kg to 3.5/4.7 mg/kg cisplatin) was similar to thiosulfate, which showed a strong inhibiting effect in the treatment of both tumors. In rats fosfomycin distinctively reduced the antitumor efficacy of cisplatin against Yoshida ascites sarcoma. Thus the concurrent injection of fosfomycin and mesna reduced both the toxicity and the antitumor activity of cisplatin. Therefore their simultaneous administration in addition to cisplatin via the same injection route should be avoided. Due to the weak detoxifying efficacy of fosfomycin and mesna they cannot be used instead of sodium thiosulfate for renal protection against cisplatin toxicity in local i.p. treatment modalities.