Sequence dependence of the antitumor and toxic effects of 5-fluorouracil and cis-diamminedichloroplatinum combination on primary colon tumors in mice

Primary colon tumors of different sizes and malignancy, chemically induced by methylazoxymethanol in outbred CF-1 mice, were used to investigate the antitumor effects of 5-Fluorouracil (5FU) and cis-diammine-dichloroplatinum (DDP), given weekly i.v. as single agents or in combination. When single-drug chemotherapy was tested, DDP showed higher efficacy than 5FU. In fact, in two separate experiments a significant reduction (P(0.05) of tumor number (TN) and tumor burden was obtained by treatment with the optimal dose of DDP (4.5 mg/kg per injection) and not by that of 5FU (52 mg/kg). When the two drugs were combined (24-h interval), studies carried out on healthy mice treated weekly i.v. showed a lower toxicity with the same doses given in the sequence 5FU-DDP than in the opposite sequence. The two drugs, delivered in the sequence 5FU followed by DDP, statistically reduced the TN and total tumor burden compared to control mice (P(0.05). On the other hand, the same doses in the sequence DDP followed by 5FU did not attain significant tumor reduction. The sequence dependence of the activity and toxicity of the 5FU and DDP combination observed in this experimental model should be taken into account in the design of clinical trials.