The sequential administration of methotrexate (MTX) and 5-fluorouracil (5-FU) (MTX/5-FU therapy) on gastric cancers has shown higher response rates than standard chemotherapy. The response rate of these cancers, however, still showed from 18 to 48%. The purpose of this study was to determine the appropriate interval time and doses of MTX/5-FU therapy using a panel of 4 cell lines originated from the poorly-differentiated gastric cancers. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used as the chemosensitivity test. The sequential administration of MTX and 5-FU inhibited the growth of 2 cell lines more than 5-FU alone. In one cell line (GCIY), it inhibited the growth 6 times, and the longest interval time (6 h) was the most effective. In the other cell line (KATOIII), it inhibited growth 3 times, and the shortest interval time (O h) was the most effective. The growth inhibition in these cases did not depend on the dose of MTX (0.01 mu g/ml to 100 mu g/ml), but on the dose of 5-FU. In conclusion, 2 out of 4 cell lines showed a synergic effect between MTX and 5-FU. While the appropriate interval time between the two drugs varied between two cell lines, 5-FU dose was more critical than that of MTX. If 5-FU dose were to be increased in future trials with MTX, its efficacy might be higher. This model should also be good to screen other anti cancer drugs combined with MTX/5-FU therapy.

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