伊立替康化学治疗的不良反应与UGT1A1＊28基因多态性的关系

目的：研究应用伊立替康化学治疗（化疗）的进展期消化道肿瘤患者不良反应的发生率及严重程度与UGT1A1基因启动子区多态性的关系。方法：选择66例汉族进展期消化道肿瘤患者,使用含伊立替康的方案化疗,观察并记录患者化疗中出现的不良反应、化疗前总胆红素水平和化疗后至Ⅲ度以上严重毒性时间（周）;外周血中抽提基因组DNA,测定UGT1A1基因启动子区TATA盒胸腺嘧啶-腺嘌呤（TA）序列重复次数,统计分析基因型与不良反应的关系,比较不同基因型患者化疗前总胆红素水平和至严重毒性时间的差异。结果：55例患者（83.3%）UGT1A1基因启动子区TA序列6次重复,为纯合野生型（TA）6/（TA）6（UGT1A1＊1/＊1）;11例患者（16.7%）基因型为TA序列6次和7次重复的杂合（TA）6/（TA）7（UGT1A1＊28/＊1）,未发现TA序列7次重复UGT1A1＊28/＊28的纯合突变。以上2组患者发生Ⅲ度以上白细胞或中性粒细胞减少者分别为26例和5例（47.3%比45.5%,P=1.000）,发生Ⅲ度以上腹泻者分别为5例和4例（9.1%比36.4%,P=0.036）。2组治疗前总胆红素水平分别为（15.1±1.1）μmol/L和（20.8±5.1）μmol/L（P=0.09）,至严重毒性时间2组分别为9周和3周（P=0.186）。结论：在应用伊立替康化疗的汉族患者中,UGT1A1启动子区TATA盒基因多态性（TA）6/（TA）7杂合状态可以增加患者发生Ⅲ度以上腹泻的风险,但不会增加患者发生Ⅲ度以上白细胞或中性粒细胞减少的风险。

A study on the relationship between the adverse events of irinotecan-based chemotherapy and UGT1A1*28 gene polymorphism

Objective To investigate the incidence and severity of adverse events in Han pateints with advanced digestive tumor treated with irinotecan-based chemotherapy, and their relationship with UGT1A1 gene promoter polymorphism. Methods Sixty-six advanced digestive tumor patients treated with irinotecan-based chemotherapy were enrolled, and the adverse events during chemotherapy, the pretreatment bilirubin level, and the time to the occurrence of degree Ⅲ toxicity were observed. Genomic DNA was extracted from peripheral blood to examine the frequency of UGT1A1 TATA box thymine-adenine (TA) repeats, and its relationship with adverse events was analyzed. The differences of the pretreatment bilirubin level and the time to the occurrence of severe toxicity were also compared. Results Fifty-five patients (83.3%) were identified with (TA)6/(TA)6 genotype, and eleven patients (16.7%) with UGT1A1*28/*1 polymorphism thymine-adenine (TA)6/(TA)7 genotype, no (TA)7/(TA)7 genotype was found]. In the two groups, 26 and 5 patients (47.3% vs 45.5%,P=1.000) had grade 3 and 4 neutropenia and 5 and 4 patients (9.1% vs 36.4% ,P--0.036) had grade 3 and 4 diarrhea, respectively. The pretreatment bilirubin levels of the two groups were (15.1±1.1) μmol/L and (20.8±5.1) μmol/L, respectively (P=0.09). The time to occurrence of severe toxicity of the two groups were 9 weeks and 3 weeks of postchemotherapy, respectively (P=0.186). Conclusions The marked increase in grade 3 or 4 diarrhea, but not in grade 3 or 4 neutropenia may occur in patients treated with irinotecan-based chemotherapy who had (TA)6/(TA)7 genotype.