Current studies of methotrexate and 5-fluorouracil and their interaction in human tumor cells.

Cell culture studies have indicated that the sequence of methotrexate (MTX) and 5-fluorouracil (5-FU) exposure influences cytotoxicity. Sequential MTX/5-FU shows synergistic effects in many cell lines, but the concentration of purines and thymidine are critical modulators of the outcome. Sequential 5-FU/MTX usually shows antagonistic cytotoxicity, and simultaneous MTX/5-FU is usually additive. The biochemical basis for the complex interaction of sequential MTX/5-FU is described, and studies of MTX/5-FU in tumor-bearing mice are reviewed. Sequential MTX/5-FU shows enhanced toxicity compared to other treatment sequences, but some studies suggest that the therapeutic index is not enhanced. Preliminary results of a randomized trial of sequential MTX/5-FU versus sequential 5-FU/MTX in cancer patients are presented.