6-巯基嘌呤致急性淋巴细胞白血病患儿不良反应及其与TPMT基因多态性的关系  

Correlations between 6-mercaptopurine treatment-related adverse reactions in children with acute lymphoblastic leukemia and polymorphisms of thiopurine methyltransferase gene

作　　者：谢偲[1] 岳丽杰[1] 丁慧[1] 任艳飞[1] 杨春兰[1] 郑苗苗[1] 

机构地区：[1]遵义医学院附属深圳市儿童医院儿科研究所,广东深圳518026

出　　处：《中国当代儿科杂志》2014年第5期499-503,共5页Chinese Journal of Contemporary Pediatrics

基　　金：深圳市科技计划重点项目(20110101);国家自然科学基金资助项目(30471830)

摘　　要：目的分析6-巯基嘌呤(6-MP)维持治疗急性淋巴细胞白血病(ALL)患儿不良反应的发生情况,探讨巯嘌呤甲基转移酶(TPMT)基因多态性与6-MP毒副作用的关系。方法提取46例ALL患儿骨髓细胞总RNA并逆转录成cDNA。应用变性梯度凝胶电泳(DGGE)结合DNA测序,对ALL患儿TPMT*1S和*3C基因型进行检测。采用美国国立癌症研究所第3版常规毒性判定标准(NCI CTC 3.0)行药物毒性分级,分析TPMT基因多态性与6-MP不良反应发生的关系。结果在维持治疗阶段,22%(10/46)患儿因6-MP所致严重不良反应停药,不良反应主要表现为骨髓抑制、肝脏毒性和胃肠道反应。2例TPMT*3C突变基因型(AG+GG)患儿均出现重度不良反应,其中1例纯和突变患儿出现与6-MP剂量相关的骨髓抑制和肝脏毒性。TPMT*1S各基因型与6-MP所致的重度骨髓抑制及肝脏毒性无明显相关性(P>0.05)。结论 TPMT*3C多态性可能与6-MP所致严重不良反应发生有关。Objective To explore 6-mercaptopurine （6-MP） treatment-related adverse reactions in children with acute lymphoblastic leukemia （ALL）, and to assess the association between the polymorphisms of thiopurine methyltransferase （TPMT） gene and these 6-MP related toxicities. Methods Total RNA was extracted from bone marrow samples of 46 children with ALL and was then reversed to cDNA. TPMT＊1S and ＊3C were screened by denaturing gradient gel electrophoresis （DGGE） combining with DNA sequencing. Drug toxicities were classified according to national cancer institute-common toxicity criteria version 3.0 （NCI CTC 3.0）. The relationship between TPMT gene polymorphisms and the adverse reactions of 6-MP treatment was analyzed. Results During the maintenance treatment period, 22% （10/46） of children discontinued 6-MP treatment because of serious adverse reactions. Two children with TPMT＊3C genotypes presented severe adverse reactions, including 1 child with homozygotic mutation who had 6-MP dose-related myelosuppression and hepatotoxicity. The main side effects of 6-MP were myelosuppression, hepatotoxicity and gastrointestinal reaction. And there were no significant differences between TPMT＊1S genotypes and severe myelosuppression or hepatotoxicity caused by 6-MP （P〉0.05）.Conclusions TPMT＊3C may correlate with severe adverse reactions caused by 6-MP.

关 键 词：6-巯基嘌呤 不良反应 巯嘌呤甲基转移酶 基因多态性 急性淋巴细胞白血病 儿童 

分 类 号：R733.71[医药卫生—肿瘤]