Biochemical modification of the toxicity and the anti-tumour effect of 5-fluorouracil and cis-platinum by WR-2721 in mice

WR-2721 (ethiofos) was tested on Balbc mice for its chemoprotective capacity against 5-fluorouracil (5FU) monotherapy. In this combination WR-2721 was not active, but WR-2721 pretreatment allowed an elevation of the cisplatin (CDDP) dose in 5FUCDDP combination therapy in these mice. Thrombocytopenia caused by the 5FUCDDP (100 and 7 mg/kg, respectively) therapy was prevented by WR-2721 (200 mg/kg) and a partial protection against leukopenia was observed in C57BI6 mice. Various WR-2721/CDDP/5FU combinations were tested on two murine colon tumour models. The best antiproliferative effect against Colon 26 (in Balbc mice) and the lowest toxicity were found with 5FU (100 mg/kg) and CDDP (5.5 mg/kg) delivered together 30 min after WR-2721 (200 mg/kg). The increased efficacy of WR-2721/CDDP/5FU both in Colon 26 and Colon 38 (in C57Bl6 mice) compared to single 5FU or 5FUCDDP treatment at the same dose could not be explained by enhanced inhibition of thymidylate synthase (TS), the 5FU target enzyme. The protection by WR-2721 against toxicity of CDDP5FU might enable the use of high doses of CDDP in this combination.