氟尿嘧啶代谢因子表达水平与进展期胃癌SOX方案新辅助化疗效果

Correlated analysis of 5 fluorouracil metabolic enzymes with tumor response after SOX regimen neoadjuvant chemotherapy in advanced gastric cancer

目的分析进展期胃癌患者新辅助化疗应用SOX方案后肿瘤组织标本氟尿嘧啶代谢因子水平变化与临床疗效的相关性。方法回顾性分析2012年6月至2013年3月解放军总医院普通外科收治的32例胃癌患者临床资料，其中，男23例、女9例，年龄56．6（40—75）岁。治疗前分期评估均为第7版美国肿瘤联合会（AJcc）Ⅱ一Ⅲ期。给予口服氟尿嘧啶（替吉奥胶囊80mg·m^-1。·d^-1，第1—14天）联合奥沙利铂（130mg／i^2，静脉滴注，第1天）新辅助化疗后进行外科手术切除，术中取得新鲜肿瘤及正常组织标本，应用实时反转录（RT）．PCR技术对氟尿嘧啶代谢因子胸腺嘧啶磷酸化酶（TP）、胸腺嘧啶合成酶（Ts）、二氢嘧啶脱氢酶（DPD）、乳清酸磷酸核糖转移酶（OPRT）的表达水平进行检＇钡4，分析其与化疗效果的相关性。结果32例患者均完成了至少2个周期新辅助化疗，21例患者肿瘤达临床缓解，有效率为65．6％（21／32）。10例患者肿瘤达组织学缓解，反应率为31．3％（10／32）。RT—PCR检测结果显示：临床缓解胃癌患者组织中OPRTmRNA表达水平高于未缓解者（3．95±0．81比1．79±0．64，P=0．005）；弥漫型胃癌患者（／2=22）胃癌组织中OPRTmRNA表达显着高于肠型胃癌（n=10）患者（2．54±0．75比1．49±0．56，P：0．014）。有淋巴结转移患者（n=13）胃癌组织中Ts、TPmRNA表达均高于无淋巴结转移（n=19）者（均P〈0．05）。而DPDmRNA各组表达差异均无统计学意义（均P〉0．05）。结论肿瘤组织中OPRTmRNA表达水平与新辅助化疗疗效相关，Ts、TP表达水平与新辅助化疗后淋巴结转移相关。OPRT、TS和TP将有可能成为进展期胃癌以氟尿嘧啶药物为基础新辅助化疗方案的有效性预测因子。

Objective To analyze the impact of mRNA expression of oral fluoropyrimidine （S-1） metabolism on treatment outcomes in locally advanced gastric cancer patients on preoperative S-1 oxaliplatin- based chemotherapy. Methods Between June 2012 and March 2013,32 patients with preoperative AJCC stage 11 - m gastric cancer patients were enrolled. They received S-1 （80 mg · m^-2 · d^-1 ,days 1 - 14） and oxaliplatin （130 mg/m2, day 1 ） every 3 weeks and subsequently underwent gastrectomy with D2 lymphadenectomy. Paired tumor and normal fresh frozen tissues were collected to evaluate the mRNA levels of thymidylate synthase （ TS）, thymidine phosphorylase （ TP）, dihydropyrimidine dehydrogenase （ DPD ） and OPRT with quantitative reverse transcription（RT） -PCR. Results Among them,21 （65.6%） patients had clinical tumor response and histological response occurred in 10 （ 31.3% ） patients. Quantitative RT-PCR results showed that OPRT mRNA expression was significantly higher in clinical tumor responders than non- responders （ 3.95 ＋ 0. 81 vs 1.79 _＋ 0. 64, P = 0. 005 ）. Diffuse-type gastric cancer patients （ n = 22 ） demonstrated higher OPRT expression levels than intestinal-type （ n = 10 ） ones （ 2. 54 ±0.75 vs 1.49 ± 0.56 ,P = 0. 014 ）. The mRNA expressions of TS and TP in gastric cancer tissues with lymph node （LN）metastasis（ n = 13 ） were significantly higher than those in gastric cancer tissues without LN metastasis（ n = 19, both P 〈 O. 05 ）. Similar results were not found for comparing dihydropyrimidine dehydrogenase expression levels （all P 〉 0. 05 ）. Conclusion OPRT, TS and TP may become potential predictive biomarkers in advanced gastric cancer patients on oral fluoropyrimidine （ S-1 ） -based chemotherapy.