Effect of thymidine on the toxicity and antitumor activity of cis-diamminedichloroplatinum (II)

The effect of thymidine (TdR) on the preclinical toxicity of cis-diamminedichloroplatinum (II) (DDP) was investigated in the BDF1 mouse and the Sprague-Dawley rat. The effect of TdR on the antitumor activity of DDP was investigated using the ascites P388 murine leukemia model. TdR at 500 mg/kg consistently decreased the recovery of body weight after DDP treatment IP, but did not affect the lethal toxicity of DDP to non-tumor-bearing mice or those with the P388 murine leukemia. This effect was greatest when TdR was injected 30 min prior to DDP and at higher doses of DDP. A 500-mg/kg dose of TdR did not affect the antitumor activity of DDP 5 mg/kg administered on days 1, 5, and 9. Treatment of rats with TdR 500 mg/kg according to various schedules of timing relative to a 5-mg/kg dose of DDP did not consistently affect the DDP-related loss in body weight or nephrotoxicity at day 3. Pretreatment of mice with TdR 1,500 mg/kg 30 min prior to DDP 5 mg/kg (every 4 days X 3) resulted in a slower recovery of body weight, which became more pronounced with increasing doses of DDP. Pretreatment of ascites P388-bearing mice with TdR 1,500 mg/kg increased the number of early deaths when mice were treated with DDP 5 mg/kg (days 1, 5, and 9). These data suggest that the cytotoxicity of DDP is increased by TdR only at higher doses of either drug, but that the antitumor activity against P388 murine leukemia is not affected.