论文部分内容阅读
Objective: Fluorouracil (5-FU) is widely used in the treatment of gastric cancer. Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthetase (TS) are important targets of many antimetabolites, including 5-FU. The relationship between polymorphism in the MTHFR (C677T, A1298C) and TS (5`-TUR, 3`-UTR) genotypes and sensitivity of gastric cancer to 5-FU-based chemotherapy is investigated in the present study. Methods: 173 patients with advanced gastric cancer were analyzed. All patients were treated with 5-FU-based chemotherapy (FOLFOX, FP and DCF regimen). DNA from peripheral blood leukocytes was obtained before the treatment. All genotypes were detected by PCR-RFLP. 12 germline polymorphisms within 2 genes were analyzed. The genotypes of MTHFR C677T, A1298C and TS 3`-TUR were analyzed in 173 patients while TS 5`-TUR in 135 patients. Results: The overall response rate (RR) was 35.8%. The RR of the DCF regimen group was signiifcantly higher than that of the FP and FOLFOX regimen groups (55.8%vs. 27.1%, 31.1%;P=0.006). The RR of the MTHFR C677T T/T genotype was signiifcantly higher than that of the C/C and C/T genotypes (73.3%vs. 28.0%;P=0.000). In MTHFR A1298C, a higher RR was observed in A/A genotype compared with the C/C and A/C genotypes (41.8%vs. 21.6%,P=0.011). The RR of-6/-6 bp and-6/+6 bp genotypes in TS 3`UTR was signiifcantly higher than that of +6/+6 bp genotype (40.3%vs. 17.6%,P=0.014). There was no difference in RR according to TS 5`UTR polymorphism (2R/2R and 2R/3R: 41.7%vs. 3R/3R: 36.8%,P=0.487). The RR of MTHFR C677T T/T genotypes in FOLFOX or FP regimens was significantly higher than that of C/C and C/T genotypes (P=0.008,P=0.000) while no difference in DCF regimen. The RR of DCF regimen wassigniifcantly higher than that of FOLFOX and FP regimens in C/T and C/C genotypes (P=0.000). The MTHFR C677T T/T genotypes had a significantly higher incidence of grade 3/4 emesis (66.7%) and stomatitis (30.0%) than patients with C/T or C/C genotypes (41.3%, 9.8%;P=0.011, 0.003). The MTHFR A1298C A/A genotype had a higher incidence of grade 3/4 stomatitis (17.2%) and diarrhea (13.9%) than patients with A/C and C/C genotypes (3.9%, 2.0%;P=0.025, 0.026). There was no difference in toxicity for patients with TS 5`UTR and TS 3`UTR genotypes.