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Schedule-dependent Antitumor Effects of Methotrexate and 5-Fluorouracil¹

Department of Pharmacology [J. R. B., C. A. L.] and Medicine [J. R. B., W. L. S., V. S. G.], Yale University School of Medicine, New Haven, Connecticut 06510

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.

¹ Supported by Grants CA-08010 and CA-08341 from the USPHS.

² American Cancer Society Research Professor.

³ Visiting Professor, Yale University School of Medicine. Present address: Department of Physiological Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Received 11/11/75. Accepted 10/ 5/76.

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