Continuous infusion of 5-fluorouracil plus low-dose cisplatin in tumor-bearing mice

Combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin is widely used but the optimal daily dose of the latter has not been established. The present study was designed to determine the pharmacodynamic interaction and antitumor effect of these drugs when used at clinically relevant doses in animals. Male ddY mice were injected with Sarcoma 180 cells and then given a continuous infusion of 5-FU (10 mg/kg/day) for 5 days (via an implanted micropump) +/- cisplatin 1 mg/kg by i.p. bolus (pharmacodynamic study). Alternatively, mice were given 5-FU +/- cisplatin (0.2 mg/kg/day), cisplatin alone for 5 days or no treatment (anti-tumor effect study). Tissue and serum samples were taken for analysis. No significant differences in serum pharmocokinetics were observed between the groups at any timepoint but 0.5 h after the start of infusion, where the serum 5-FU concentration was lower with monotherapy than with combination therapy. 5-FU alone had a slight antitumor effect, while low-dose cisplatin alone had no noticeable effect. 5-FU + cisplatin produced a favorable response, with a significantly lower treated/control tumor weight ratio than in the non-treated and cisplatin monotherapy groups (p < 0.05), although this was not significantly different from the response to 5-FU monotherapy. In conclusion, the dose of cisplatin used in the present study was insufficient to generate a significant tumor response alone but it did tend to enhance the antitumor efficacy of 5-FU. Continuous 5-FU infusion plus low-dose daily cisplatin may become clinically useful after further investigation.