Sequence-dependent synergism between dichloromethotrexate and 5-fluorouracil in a human colon carcinoma cell line

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 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.