Schedule-dependent antitumor effects of methotrexate and 5-fluorouracil

The antitumor effects of methotrexate with 5-fluorouracil against the Sarcoma 180 mouse tumor model were found to be schedule dependent. Pretreatment of tumor-bearing animals with methotrexate significantly enhanced the antitumor activity of the combination relative to simultaneous treatment or to those with methotrexate following 5-fluorouracil. These studies indirectly support the hypothesis that methotrexate pretreatment with 5-fluorouracil is synergistic by increasing the amount of thymidylate synthetase bound to the active metabolite of 5-fluorouracil.