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

【目的与方法】据报道，5-氟尿嘧啶（5-FU）的代谢酶胸腺苷酸合成酶（TS）或二氢嘧啶脱氢酶（DPD）的肿瘤活性与5-FU的敏感性或患者的预后有关。然而，癌细胞暴露于5-FU后，这种5-FU代谢酶的活性可能发生变化，也可能影响细胞对5-FU的反应。在本研究中，我们测量了胃癌患者术前使用UFT （5-FU前药替加富与尿嘧啶按1:4的比例组成）化疗前后肿瘤中TS/DPD mRNA的表达，旨在阐明这种TS/DPD mRNA的表达水平是否与UFT的组织学疗效相关。在另一项实验研究中，我们研究了胃癌细胞暴露于5-FU时5-FU代谢酶活性的可能扰动，并研究了其与5-FU敏感性的关系。【结果】5-FU对胃癌患者和培养的胃癌细胞的肿瘤TS和DPD水平均有影响。在临床研究中，UFT给药前低DPD mRNA水平与良好的组织学效果相关，而TS mRNA水平与各病例的组织学效果无关。在实验研究中，5-FU暴露期间TS总/抑制率的升高或DPD水平的降低与培养的胃癌细胞对5-FU的敏感性相关。【意义】5-FU暴露诱导的TS和DPD水平的不同改变可能是决定胃癌细胞对5-FU敏感性或耐药性的关键反应，但这种改变的分子机制尚未阐明。

[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.