The combined effects of methotrexate and 5-fluoropyrimidines on the growth of a human breast cancer cell line in serum-free hormone-supplemented medium, lacking nucleosides, have been studied. All combinations of methotrexate (10-50 nM) and 5-fluorodeoxyuridine (10-100 nM) resulted in at least additive inhibition of cell growth and when analyzed by 50% response isobologram demonstrated synergism. Combinations of methotrexate (10-50 nM) and 5-fluorouracil (0.04-0.4 μM) gave enhanced inhibition as compared to single agents, but 50% response isobologram revealed only additive effects. The combination was most effective when methotrexate was added to the cultures prior to the 5-fluoropyrimidines or when the drugs were added simultaneously. The addition of 5-fluoropyrimidine prior to methotrexate appears to decrease the effect of the antifol on purine synthesis and lessen the cytotoxicity of the combination in this cell line.
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