尿苷二磷酸葡萄糖醛酸转移酶1A1＊28基因多态性和伊立替康毒副反应相关性研究  

Study of irinotecan-induced toxicity and its correlation to UGT1A1 ＊ 28 gene promoter polymorphisms

作　　者：秦琼[1] 杨林[1] 周爱萍[1] 黄镜[1] 张雯[1] 孙永琨[1] 王金万[1] 

机构地区：[1]中国医学科学院 北京协和医学院 肿瘤医院内科,北京100021

出　　处：《癌症进展》2013年第4期369-373,387,共6页Oncology Progress

摘　　要：目的 初步了解肿瘤患者血中尿苷二磷酸葡萄糖醛酸转移酶1A1 （UGT1A1）启动子的多态性分布,并研究其多态性和伊立替康化疗的毒副反应之间的关系.方法 收集拟采用伊立替康为基础化疗方案的患者全血标本,直接测序分析UGT1A1＊ 28 TATA盒基因序列；并与化疗毒副反应进行相关性分析.结果 203例患者进行UGT1A1＊ 28 TATA基因启动子检测,UGT1A1＊ 28野生纯合型（TA6/6）最常见,共156例,占76.8％；其次为突变杂合型（TA6/7）,共43例,占21.2％；突变纯合型（TA7/7）仅3例,占1.5％；TA5/6有1例,占0.5％.共有183例患者使用含伊立体康方案治疗.突变纯合型（TA7/7）与3度及以上迟发型腹泻和中性粒细胞减少明确相关（P =0.001、P=0.048）,与化疗前总胆红素水平升高相关（P＜0.001）；突变杂合型（TA6/7）和野生纯合型（TA6/6）在3度及以上迟发型腹泻和中性粒细胞减少方面的相关性类似（P =0.561、P=0.915）,化疗前总胆红素水平类似（P =0.229）.结论 UGT1A1＊ 28突变纯合型（TA7/7）明显增加伊立替康所致3度及以上延迟性腹泻和中性粒细胞减少,增加化疗前胆红素水平；而UGT1A1＊ 28突变杂合型（TA6/7）并不增加3、4度迟发型腹泻和粒细胞减少的发生及化疗前总胆红素水平.Objective To investigate the polymorphistic distribution of uridine diphosphate-glucuronosylyransferase1A1 （UGT1A1） gene promoter and its relation to the toxicities caused by irinotecan in Chinese patients with advanced gastrointestinal carcinoma.Method Whole blood samples were taken from all the 203 patients with advanced gastrointestinal carcinoma.The adverse events were recorded to compare the incidence of grades 3 and 4 adverse events.Result 156 （76.8％） were identified as having homozygous wild-type TA6/6 in the promoter region at position 28 of the UGT1A1 gene,43 （21.2％） were found to have heterozygous type TA6/7,and 3 （1.5％） carried homozygous mutant-type TA7/7,and 1 （0.5％） carried TA6/5.183 patients accepted chemotherapy containing irinotecan-based regime.Marked increases in diarrhea and neutropenia higher than 3 grade and the level of total bilirubin were observed in patients carrying the TA7/ 7 genotype （P =0.001,P =0.048 and P ＜ 0.001）.There were no difference between the TA6/6 and the TA6/7 genotypes in diarrhea and neutropenia and the level of total bilirubin （P =0.561,P =0.915 and P =0.229）.Conclusion The present study demonstrated that the homozygous TA7/7 genotype of UGT1 A1 ＊ 28 increases the risk of developing grade 3 or more severe diarrhea and neutropenia and the level of total bilirubin for the patients receiving irinotecan-based chemotherapy.

关 键 词：葡萄糖醛酸基转移酶1A1 伊立替康 腹泻 中性粒细胞减少 

分 类 号：R730.53[医药卫生—肿瘤]