Capitain O, Boisdron-Celle M, Poirier A-L, Abadie-Lacourtoisie S, Morel A, Gamelin E
Department of Medical Oncology and Clinical Pharmacology, INSERM U564 Centre Paul Papin, Centre Régional de Lutte Contre le Cancer, Angers, Cedex, France.
Pharmacogenomics J. 2008 Aug;8(4):256-67. doi: 10.1038/sj.tpj.6500476. Epub 2007 Aug 14.
The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status >2 (P=0.004), low UH2/U ratio, 2846 A>T, IVS 14+1G>A for DPD (P=0.031), and homozygoty C/C for MTHFR 1298 A>C (P=0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C>T or A/A for 1298 A>C was statistically shorter (log-rank test P=0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature.
本研究的目的是确定有助于调整5-氟尿嘧啶（5-FU）给药方案的简单遗传因素，并确定晚期结直肠癌一线化疗的策略。在76例最初接受5-FU治疗的患者中，研究了胸苷酸合成酶、二氢嘧啶脱氢酶和亚甲基四氢叶酸还原酶的胚系多态性、二氢尿嘧啶/尿嘧啶血浆比率以及5-FU血浆清除率，并将其与耐受性（10.5%为3级和4级毒性）和疗效（32.9%的客观缓解率和20个月的中位总生存时间）进行关联分析。毒性与体能状态>2（P=0.004）、低UH2/U比率、DPD的2846 A>T、IVS 14+1G>A（P=0.031）以及MTHFR 1298 A>C的纯合子C/C（P=0.0018）相关。对于677 C>T为C/C或1298 A>C为A/A的患者，3R/3R TS基因型患者的总生存期在统计学上较短（对数秩检验P=0.0065）。遗传因素有助于调整5-FU治疗方案。在未来针对具有特定生物学特征患者进行专门治疗设计的临床试验中，它们应占据核心地位。
