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Sequence-dependent Synergism between Dichloromethotrexate and 5-Fluorouracil in a Human Colon Carcinoma Cell Line¹

Yale University School of Medicine, Department of Pharmacology, New Haven, Connecticut 06510

Prior to their use in patients with hepatic metastasis of colon cancer, we studied the cell-killing effects of 5-fluorouracil, 5-fluoro-2'-deoxyuridine, 3',5'-dichloromethotrexate (DCM), and combinations of these fluoropyrimidines with DCM on a human colon carcinoma cell line (HCT-8). Sequential exposure of these cells to DCM followed by 5-fluorouracil resulted in significant synergistic cell killing at every dose and time studied, and the synergy was more evident with increasing doses of both drugs. In contrast, simple additive effects were observed when DCM was given together with or following 5-fluorouracil. When the antifolate was given before 5-fluoro-2'-deoxyuridine, simple additive effects, rather than synergy, were observed. Mild antagonism and even strong antagonism were found when 5-fluoro-2'-deoxyuridine preceded DCM administration or when the cells were exposed to the drugs simultaneously, respectively.

¹ Supported by Grant CA 24887-05.

² Fellow of the Associazione Italiana per la Ricerca sul Cancro.

³ American Cancer Society Professor. To whom requests for reprints should be addressed, at Yale University School of Medicine, Department of Pharmacology, P.O. Box 3333, 333 Cedar Street, New Haven, Conn. 06510.

Received 2/17/83. Accepted 5/25/83.