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目的观察亚甲基四氢叶酸还原酶(MTHFR)(C677T、A1298C)和胸苷酸合成酶(TS 3’-UTR)多态与5-FU为基础化疗方案及晚期胃癌敏感性的关系。方法选取173例晚期胃癌患者,所有病例均接受5-FU为基础化疗方案(FOLFOX,FP和DCF方案)化疗。在化疗前获取外周血白细胞DNA。采用PCR-RELP检测基因型。在2个基因中共检测了9种遗传多态。173例中检测了MTHFR(C677T、A1298C)和TS(3’-TUR)多态。结果所有患者化疗总有效率为35.8%。DCF方案的有效率显著高于FP和FOLFOX方案(55.8%vs 27.1%,31.1%;P=0.006)。MTHFR C677T T/T基因型患者的有效率显著高于C/C和C/T基因型(73.3%vs 28.0%;P=0.000)。在MTHFR A1298C中,A/A基因型患者的有效率显著高于C/C和A/C基因型(41.8%vs 21.6%,P=0.011),在TS 3’-UTR中,-6/-6bp和-6/+6bp基因型患者的有效率显著高于+6/+6 bp基因型(40.3%vs 17.6%,P=0.014)。FOLFOX和FP方案中,MTHFR C677T T/T基因型患者的有效率均显著高于C/C和C/T基因型(P=0.008;P=0.000),但在DCF方案中没有发现差异。在MTHFR C/T和C/C基因型中,DCF方案的有效率显著高于FP和FOLFOX方案(P=0.000)。MTHFR C677T T/T基因型患者的Ⅲ-Ⅳ度呕吐(66.7%)和口腔炎(30.0%)发生率显著高于C/C和C/T基因型(41.3%,9.8%;P=0.011,0.003)。MTHFR A1298C A/A基因型患者的Ⅲ-Ⅳ度口腔炎(17.2%)和腹泻(13.9%)发生率同样显著高于A/C和C/C基因(3.9%,2.0%;P=0.025,0.026)。TS 3’-UTR的不同多态之间没有发现毒性差异。结论检测外周血白细胞DNA中的MTHFR和TS基因多态能预测以5-FU为基础化疗方案治疗晚期胃癌的有效性和化疗相关的毒性反应。
Objective To investigate the relationship between polymorphisms of methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C) and thymidylate synthase (TS 3’-UTR) and 5-FU-based chemotherapy regimen and the sensitivity of advanced gastric cancer. Methods A total of 173 patients with advanced gastric cancer were enrolled in this study. All patients underwent chemotherapy with 5-FU-based chemotherapy (FOLFOX, FP and DCF regimens). Peripheral blood leukocyte DNA is obtained before chemotherapy. Genotypes were detected by PCR-RELP. Nine genetic polymorphisms were detected in two genes. Of 173 cases, MTHFR (C677T, A1298C) and TS (3’-TUR) polymorphisms were examined. Results The total effective rate of chemotherapy in all patients was 35.8%. The efficiency of the DCF regimen was significantly higher than that of the FP and FOLFOX regimens (55.8% vs 27.1%, 31.1%; P = 0.006). Patients with MTHFR C677T T / T genotype were significantly more effective than C / C and C / T genotypes (73.3% vs 28.0%; P = 0.000). In MTHFR A1298C, the efficiency of A / A genotype patients was significantly higher than that of C / C and A / C genotypes (41.8% vs 21.6%, P = 0.011) Patients with 6bp and -6 / + 6bp genotypes were significantly more effective than the + 6 / + 6 bp genotype (40.3% vs 17.6%, P = 0.014). In the FOLFOX and FP regimens, the efficiency of the MTHFR C677T T / T genotype was significantly higher for the C / C and C / T genotypes (P = 0.008; P = 0.000), but no differences were found in the DCF regimen. In the MTHFR C / T and C / C genotypes, the efficiency of the DCF regimen was significantly higher than that of the FP and FOLFOX regimens (P = 0.000). The incidence of grade Ⅲ-Ⅳ vomiting (66.7%) and stomatitis (30.0%) in MTHFR C677T T / T genotype was significantly higher than that in C / C and C / T genotypes (41.3%, 9.8% 0.003). The incidence of grade Ⅲ-Ⅳ stomatitis (17.2%) and diarrhea (13.9%) in patients with MTHFR A1298C A / A genotype was also significantly higher than those in A / C and C / C genes (3.9%, 2.0% 0.026). Toxic differences were not found between the different polymorphisms of the TS 3’-UTR. Conclusion Detection of polymorphisms of MTHFR and TS in peripheral leukocyte DNA can predict the efficacy of 5-FU-based chemotherapy in the treatment of advanced gastric cancer and chemotherapy-related toxicities.