The role of drug sequence in therapeutic selectivity of the combination of 5-fluorouracil and cis-platin.

The therapeutic efficacy of 5-fluorouracil (FUra) and cis-dichlorodiamine-platinum (cis-DDP) in mice bearing transplantable leukemia and solid tumors was evaluated using different sequences of combination of these agents. The optimal sequence was cis-DDP administered 24 h after FUra. The administration of FUra at its maximally tolerated dose (MTD) followed 24 h later by low doses of cis-DDP yielded less toxicity and higher response rate against L1210 and colon 26 than the administration of these two agents in the opposite sequence or concurrently at the MTD. The sequence of administration of these two agents was not therapeutically important when the antitumor activity was evaluated against mice bearing lymphoma P388. These results indicate that the importance of sequencing of FUra and cis-DDP varies among different tumors. The biochemical basis for the therapeutic importance of sequencing in treatments with cis-DDP and FUra was investigated in mice bearing leukemia L1210 cells. While cis-DDP has no significant effects on the activity of thymidylate synthase (dTMP-S), the target enzyme for FUra action, recovery of dTMP-S inhibition following pretreatment with FUra was significantly delayed when cis-DDP was administered 12-24 h after the initial dose of FUra.