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Synergism of Methotrexate with Imuran and with 5-Fluorouracil and Their Effects on Hemolysin Plaque-forming Cell Production in the Mouse¹

Department of Medicine, Roger Williams General Hospital, Providence, Rhode Island 02908, and Division of Bio-Medical Sciences, Brown University, Providence, Rhode Island 02912

The present study has provided evidence that the administration of methotrexate (MTX) and 5-fluorouracil (5-FU) together in the proper regimen results in a synergistic suppression of 19 S hemolysin plaque-forming cell production. A similar effect was demonstrated when a combination of Imuran (IM) and MTX was used although the degree of potentiation was not as great. The administration of MTX (1 mg/kg) 15 min prior to the administration of 5-FU (50 mg/kg) resulted in very strong (90%) inhibition of hemolysin plaque-forming cell production in C3HeB/FeJ female mice. If the direction of administration was reversed, that is 5-FU before MTX, particularly when the interval between the two was less than 6 hr, little inhibition was observed (12 to 30%). The interaction of IM and MTX was synergistic if IM was given prior to MTX but additive if IM was given after MTX. These types of drug-drug interactions may prove useful in the control of immune reactions, in particular, the production of serum-blocking factor. Such a potent inhibitor of humoral antibody production may provide a beneficial shift of tumor immunity in favor of the host.

¹ This work was supported by the Clinical and Biochemical Pharmacology Grant GM16538-05, USPHS (General Medical Sciences), and the Clinical Pharmacology-Immunology Cancer Research Center Grant 1-PO2-CA-13943-01 CAP.

Received 10/ 5/73. Accepted 12/11/73.

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