Reduction of cisplatin toxicity and lethality by sodium malate in mice

The effects of oral treatment with sodium malate, an active ingredient of Juzen-taiho-to, on the nephrotoxicity, bone marrow toxicity, hepatotoxicity and gastrointestinal toxicity caused by i.p. administration of 9 doses of 3.0 mg/kg/d cisplatin (CDDP) (on days 3, 4, 5, 6, 7, 8, 10, 11 and 12) were examined in ddY mice inoculated with sarcoma 180 (S-180) cells on day 1 of the study. The CDDP-induced increases in blood urea nitrogen, serum creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminases and relative stomach weight and the decreases in food intake and body weight were inhibited nearly to the control levels without reducing the antitumor activity of CDDP against S-180 by the oral treatment with sodium malate of 12 doses of more than the equimolar amount of CDDP (on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 and 15). However, the CDDP-induced decreases in white blood cell and platelet counts and relative spleen and thymus weight could not be inhibited completely by combination with sodium malate, even at a dose of twice the equimolar amount of CDDP. The sodium malate-induced reduction of CDDP-induced nephrotoxicity and hepatotoxicity was observed after oral administration, as well as with i.p., s.c. and i.v. administration, and the effect was almost the same for each route of administration. Sodium malate also reduced the toxicity induced by high doses of CDDP (4.5, 6.0, 7.5, 9.0 and 12.0 mg/kg/d) at doses of twice the equimolar amount of CDDP. Sodium malate at a dose of 10.68 mg/kg/d (twice as high as carboplatin, CBDCA) did not reduce the nephrotoxicity, bone marrow toxicity, hepatotoxicity and gastrointestinal toxicity caused by i.p. administration of 9 doses of 15.0 mg/kg/d CBDCA on days 3, 4, 5, 6, 7, 8, 10, 11 and 12 in ddY mice inoculated with sarcoma 180 (S-180) cells on day 1 of the study. From this study, it was suggested that sodium malate could become a useful agent for the reduction of CDDP-induced toxicity, particularly nephrotoxicity and hepatotoxicity.