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

基于 5-FU 胃癌化疗疗效预测的术后辅助化疗研究。

• 批准号: 12671199
• 负责人: NABEYA Yoshihiro
• 金额: $ 1.98万
• 依托单位: CHIBA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671199/
• 关键词: 5-FU; thymidylate synthase (TS); dihydropyrimidine dehydrogenase (DPD); thymidine phosphorylase (TP); GASTRIC CANCER; HISTOLOGICAL EFFECT; DRUG SENSITIVITY; p53; Thymidylate synthase (TS); TS阻害率; Dihydropyrimidine dehydrogenase (DPD); Thymidine

[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.

[目的与方法]胸苷酸合成酶（TS）或二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（5-FU）的代谢酶，其肿瘤活性与患者对5-FU的敏感性和预后有关。然而，由于癌细胞暴露于5-FU而导致的这种5-FU代谢酶的活性的可能变化也可能影响对5-FU的细胞应答。在本研究中，我们测量了胃癌患者术前用UFT（包括5-FU前药替加氟和尿嘧啶，比例为1：4）化疗前后肿瘤TS/DPD mRNA的表达，旨在阐明这种TS/DPD mRNA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，我们检查了胃癌细胞暴露于5-FU期间5-FU代谢酶活性的可能扰动，并研究了与5-FU敏感性的相关性。[结果] 5-FU治疗后，胃癌患者和培养的胃癌细胞中TS和DPD水平均发生变化。在临床研究中，UFT给药前低DPD mRNA水平与良好的组织学效应相关，而TS mRNA水平与每种情况下的组织学效应无关。在实验研究中，无论是TS总/抑制率的升高，还是DPD水平的降低，都与培养的胃癌细胞对5-FU的敏感性有关。[意义] 5-FU暴露诱导的TS和DPD水平的不同变化可能是决定胃癌细胞对5-FU敏感或耐药的关键反应，但其分子机制尚未阐明。

项目成果

Nabeya, Y., et al.: "Is an alteration in the activity of 5-FU-metabolizing enzymes a critical response to 5-FU treatment in esophageal/gastric cancer cell lines? Implications for 5-FU sensitivity."Proc.Am.Assoc.Cancer Res.. 44. 4599 (2003)

Nabeya, Y. 等人：“5-FU 代谢酶活性的改变是食管/胃癌细胞系对 5-FU 治疗的关键反应吗？对 5-FU 敏感性的影响。”Proc.Am

Nabeya, Y., et al.: "Is an alteration in the activity of 5-FU-metabolizing enzymes a critical response to 5-FU treatment in esophageal/gastric cancer cell lines? Implications for 5-FU sensitivity."Proc.Am.Assoc.Cancer Res. (1st ed.). 44. 4599 (2003)

Nabeya, Y. 等人：“5-FU 代谢酶活性的改变是食管/胃癌细胞系对 5-FU 治疗的关键反应吗？对 5-FU 敏感性的影响。”Proc.Am