Ruzzo A, Graziano F, Loupakis F, Santini D, Catalano V, Bisonni R, Ficarelli R, Fontana A, Andreoni F, Falcone A, Canestrari E, Tonini G, Mari D, Lippe P, Pizzagalli F, Schiavon G, Alessandroni P, Giustini L, Maltese P, Testa E, Menichetti E T, Magnani M
Institute of Biochemistry G Fornaini, University of Urbino, Urbino, Italy.
Pharmacogenomics J. 2008 Aug;8(4):278-88. doi: 10.1038/sj.tpj.6500463. Epub 2007 Jun 5.
The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56-5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.
本研究的主要终点是分析对5-氟尿嘧啶/伊立替康活性可能有影响的多态性与接受一线FOLFIRI化疗的晚期结直肠癌患者无进展生存期（PFS）之间的关联。对146例前瞻性入组患者的外周血样本进行了胸苷酸合成酶（TS）、亚甲基四氢叶酸还原酶（MTHFR）、切除修复交叉互补组1（ERCC 1）、着色性干皮病D组（XPD）、X射线交叉互补蛋白1（XRCC 1）、X射线交叉互补蛋白3（XRCC 3）和尿苷二磷酸葡萄糖醛酸转移酶A1（UGT1 A1）基因多态性的基因分型。TS 3'-UTR 6+/6+和XRCC3 - 241 C/C基因型与不良PFS相关。在30例（20%）具有两种风险基因型的患者中，PFS的风险比达到2.89（95%置信区间=1.56 - 5.80；P = 0.002）。III - IV级中性粒细胞减少的风险与UGT1A1*28 7/7基因型显著相关。这些有前景的发现值得进一步研究，并在独立的前瞻性研究中进行验证。
