Effect of coadministration of selenite on the toxicity and antitumor activity ofcis-diamminedichloroplatinum(II) given repeatedly to mice

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Abstract
The effect of selenite coadministration on the toxicity and antitumor activity of repeated treatment with high doses ofcis-diamminedichloroplatinum (cis-DDP) was examined in mice. Sodium selenite was injected s.c. into separate abdominal sites of mice together withcis-DDP at a molar ratio of 1:3.5 (selenite tocis-DDP) on day 0. The same amount of selenite was given daily for 4 subsequent days (days 1–4). This fixed administration schedule was repeated weekly for a total of 7 weeks. Under the experimental conditions used, the lethal toxicity, renal toxicity [indicated by an increase in blood urea nitrogen (BUN) and plasma creatinine levels], hepatic toxicity (indicated by an increase in plasma GPT and GOT activity), and myelotoxicity (indicated by a decrease in the numbers of leukocytes and platelets) observed in mice given repeated doses ofcis-DDP alone (15 or 25 μmol/kg, s.c.) were significantly depressed by the coadministration of sodium selenite. Treatment withcis-DDP alone (15,20, or 25μmol/kg, s.c.) resulted in some dose-dependent prolongation of the life span of mice transplanted either s.c. with colon adenocarcinoma 38 (colon 38) or i.p. with P388 leukemia (P388) but did not completely depress the tumor growth, and the animals died of either progressive disease orcis-DDP-induced toxicity. However, following the coadministration of 7.1 μmol/kg selenite with 25 μmol/kgcis-DDP, all of the mice transplanted either s.c. with colon 38 or i.p. with P388 survived for as long as 4 months after the end of the treatment and showed no evidence of malignancy. These results indicate that selenite coadministration enables the use of increasing doses ofcis-DDP and, consequently, enhances the antitumor effect ofcis-DDP by depressing its side effects.