STUDIES OF POSTOPERATIVE ADJUVANT CHEMOTHERAPY BASED ON THE PREDICTION OF EFFICACY OF 5-FU-BASED CHEMOTHERAPY FOR GASTRIC CANCER.

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[Purpose and methods] The tumoral activity of thymidylate synthase (TS) or dihydropyrimidine dehydrogenase (DPD), the metabolizing enzyme of 5-fluorouracil (5-FU), has reportedly been related to either the sensitivity to 5-FU or the prognosis of the patient. However, possible changes in the activity of such 5-FU-metabolizing enzymes resulting from an exposure of cancer cells to 5-FU may also affect the cellular response to 5-FU. In the present study, we measured the tumoral mRNA expressions of TS/DPD in gastric cancer patients before and after preoperative chemotherapy with UFT (comprising 5-FU prodrug tegafur and uracil at a ratio of 1:4), and aimed to clarify whether such TS/DPD mRNA expression levels could be correlated with the histological efficacy of UFT. In another experimental study, we examined possible perturbations in the activity of 5-FU-metabolizing enzymes during an exposure of gastric cancer cells to 5-FU, and the association with sensitivity to 5-FU was investigated. [Results] The tumoral TS and DPD levels were found to be altered by 5-FU treatment in both of gastric cancer patients and cultured gastric cancer cells. In the clinical study, the low DPD mRNA level before administration of UFT correlated with the favorable histological effect, while the TS mRNA level did not correlate with the histological effect in each case. In the experimental study, either elevation of TS total/inhibition rate or low level of DPD during 5-FU exposure was associated with sensitivity to 5-FU in cultured gastric cancer cells. [Significance] The different alterations in the TS and DPD levels induced by 5-FU exposure may be a critical response defining the sensitivity or resistance for 5-FU in gastric cancer cells, while the molecular mechanisms of such alterations have yet to be elucidated.