Polymorphisms in the methotrexate transport pathway: a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia.
Polymorphisms in the methotrexate transport pathway: a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia.
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DOI：
10.1097/fpc.0b013e32835c3b24
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发表时间：
2013-02-01
影响因子：
2.6
通讯作者：
Garcia-Orad, Africa
中科院分区：
文献类型：
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作者：
Lopez-Lopez, Elixabet;Ballesteros, Javier;Garcia-Orad, Africa
目的：甲氨蝶呤（MTX）是治疗小儿急性淋巴细胞白血病（ALL）的重要组成部分。 MTX 治疗通常会引起毒性，可能需要减少剂量或停止治疗。不良反应的个体差异可能是由不同因素造成的，包括关键基因的多态性。最近，我们证实了 Trevino 及其同事先前提出的 SLCO1B1 rs11045879 多态性与毒性之间的关联。由于 SLCO1B1 是参与 MTX 消除的转运蛋白，因此该途径基因中的其他多态性也可能在 MTX 毒性中发挥作用。本研究的目的是深入分析 MTX 转运途径基因多态性作为儿科 ALL 假定毒性预测因子的作用。 方法：我们分析了 12 个转运蛋白基因（SLCO1B1、SLCO1B3、SLCO1A2、ABCB1、ABCG2、ABCC1、ABCC2、ABCC3、ABCC4、SLC19A1、 SLC22A6 和 SLC22A8）及其与使用 LAL/SHOP 方案治疗的 151 名儿童 ALL 患者中不同毒性参数的相关性。 结果：发现来自 7 个基因和 15 个单倍型的 21 个多态性与 MTX 血浆水平显着相关。校正后，ABCC4 中的 rs9516519、ABCC2 中的 rs3740065 和 ABCC2 中的单倍型 GCGGG 仍然显着相关。结论：我们的结果表明，ABCC4 和 ABCC2 中的多态性可能是儿科 ALL 中 MTX 毒性的新标志物。
OBJECTIVES: Methotrexate (MTX) is an important component of therapy for pediatric acute lymphoblastic leukemia (ALL). Treatment with MTX often causes toxicity, which can necessitate dose reduction or treatment cessation. Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes. Recently, we confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity previously proposed by Trevino and colleagues. As SLCO1B1 is a transporter involved in MTX elimination, other polymorphisms in genes from this pathway could also have a role in MTX toxicity. The aim of the present study was to analyze in depth the role of polymorphisms in the genes of the MTX transport pathway as putative toxicity predictors in pediatric ALL.METHODS: We analyzed 384 single nucleotide polymorphisms in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3, ABCC4, SLC19A1, SLC22A6 and SLC22A8) and their correlation with different toxicity parameters in 151 pediatric ALL patients treated using the LAL/SHOP protocol.RESULTS: A significant association with MTX plasma levels was found for 21 polymorphisms from seven genes and 15 haplotypes. After correction, rs9516519 in ABCC4, rs3740065 in ABCC2, and haplotype GCGGG in ABCC2 remained significantly associated.CONCLUSION: Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.