Objective: To investigate the correlation between UGT1A1 polymorphisms and the irinotecan plus S-1 regimen-induced toxicities in Chinese advanced esophageal squamous cell carcinoma (ESCC) patients. Methods: A total of 46 recurrent or metastatic ESCC patients selected from ESWN 01 trial were randomly assigned to irinotecan plus S-1 group [intravenous infusion of irinotecan (160 mg/m(2)) on day 1 and oral S-1 (80-120 mg) on days 1-10, repeated every 14 days]. Peripheral venous blood at baseline was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6 and UGT1A1*28 were analyzed by polymerase chain reaction (PCR) amplification. Irinotecan plus S-1 regimen-induced toxicities of patients with different UGT1A1 polymorphisms were observed. The correlation between UGT1A1 polymorphisms and the adverse effects was analyzed. Results: Among the 46 patients, the numbers of UGT1A1*6 wild type genotype (GG), mutant heterozygote (GA) and mutant homozygote (AA) were 30, 15 and 1, while those with UGT1A1*28 wild type genotype (TA6/6), mutant heterozygote (TA6/7) and mutant homozygote (TA7/7) were 36, 8 and 2, respectively. Only one patient with UGT1A1*6 AA genotype occurred grade 3 diarrhea, while one of the 2 patients with UGT1A1*28 TA7/7 genotype occurred grade 4 diarrhea. No neutropenia was observed in the patient with UGT1A1*6 AA genotype, however, both of the two patients with UGT1A1*28 TA7/7 genotype occurred grade 3-4 neutropenia. Patients with UGT1A1*28 genetic polymorphism (TA 6/7 or TA7/7) had a higher response rate compared with wild-type TA6/6 carriers. (55.6% versus 26.5%). Conclusions: The homozygous genotype of UGT1A1*6 AA and UGT1A1*28 TA7/7 are rare (<5%) in Chinese ESCC population. Not all homozygous AA and TA7/7 carriers occur severe dose limited toxicities (DLT) when treated with irinotecan (160 mg/m(2)) plus S-1 regimen for 2 weeks. However, it's still necessary torigorously observe the occurrence of severe diarrhea and neutropenia in patients with UGT1A1*6 AA and UGT1A1*28 TA7/7 and adjust the dose timely.
目的： 探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因多态性与伊立替康联合替吉奥治疗晚期食管鳞癌所致不良反应的关系。 方法： 选取ESWN 01研究中伊立替康联合替吉奥治疗组(伊立替康160 mg/m(2)，第1天；替吉奥胶囊80~120 mg/d，第1~10天；每14 d重复)的46例晚期食管鳞癌患者，观察化疗期间出现的剂量限制性不良反应，采用聚合酶链反应检测UGT1A1*6和UGT1A1*28基因型，分析UGT1A1基因多态性与不良反应的关系。 结果： 46例患者中，UGT1A1*6野生型(GG)、杂合突变型(GA)、纯合突变型(AA)患者分别为30、15和1例，UGT1A1*28野生型(TA6/6)、杂合突变型(TA6/7)、纯合突变型(TA7/7)患者分别为36、8和2例。仅有的1例UGT1A1*6纯合突变型患者出现3级迟发性腹泻，未出现骨髓抑制。2例UGT1A1*28纯合突变型患者，均发生3~4级中性粒细胞减少，其中1例发生3级迟发性腹泻。UGT1A1*28突变型(TA6/7和TA7/7)患者的客观缓解率为55.6%(5/9)，高于野生型(TA6/6)患者[26.5%(9/34)]。 结论： 中国食管鳞癌患者中，UGT1A1*6和UGT1A1*28纯合突变均十分少见(<5%)。给予伊立替康(160 mg/m(2))联合替吉奥2周方案治疗后，纯合突变型食管鳞癌患者并不都发生严重的剂量限制性不良反应。但对UGT1A1*6和UGT1A1*28纯合突变型患者仍需密切监测严重迟发性腹泻和骨髓抑制的发生，并及时作出剂量调整。.
Keywords: Adverse events; Diarrhea; Esophageal squamous cell carcinoma; Gene polymorphisms; Irinotecan; Neutropenia; Uridine diphosphate glucoronosyltransferase 1A1.