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

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^*S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。

Abstract:

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.