Association of ABCC2 -24C>T polymorphism with high-dose methotrexate plasma concentrations and toxicities in childhood acute lymphoblastic leukemia.
Association of ABCC2 -24C>T polymorphism with high-dose methotrexate plasma concentrations and toxicities in childhood acute lymphoblastic leukemia.
复制标题
DOI：
10.1371/journal.pone.0082681
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Liu Y;Yin Y;Sheng Q;Lu X;Wang F;Lin Z;Tian H;Xu A;Zhang J
甲氨蝶呤（MTX）是治疗儿童急性淋巴细胞白血病（ALL）的关键药物。甲氨喋呤血浆浓度升高与药物不良反应的高风险相关。atp结合盒亚家族C成员2 （ABCC2）对MTX及其毒性代谢物的排泄很重要。据报道，ABCC2−24C>T多态性（rs717620）有助于MTX动力学的变异性。在本研究中，我们评估了接受大剂量甲氨蝶呤治疗的儿童ALL患者ABCC2−24C>T多态性与甲氨蝶呤（MTX）毒性之间的关系。根据ALL- berlin - frankfurt - muenster 2000方案，共有112名汉族ALL患者接受高剂量MTX治疗。我们的研究结果表明，ABCC2基因中−24T等位基因的存在导致在开始输注后48小时MTX血浆浓度显著升高，并且在重复输注MTX时浓度会增强。ABCC2基因中的- 24T等位基因与高级别血液学（白细胞减少、贫血和血小板减少）和非血液学（胃肠道和粘膜损伤/口腔粘膜炎）MTX毒性的高风险显著相关。本研究首次提供了ABCC2基因- 24T等位基因与MTX毒性严重程度相关的证据，为大剂量MTX的临床应用和MTX治疗的个体化提供了新的见解。
Methotrexate (MTX) is a key agent for the treatment of childhood acute lymphoblastic leukemia (ALL). Increased MTX plasma concentrations are associated with a higher risk of adverse drug effects. ATP-binding cassette subfamily C member 2 (ABCC2) is important for excretion of MTX and its toxic metabolite. The ABCC2 −24C>T polymorphism (rs717620) reportedly contributes to variability of MTX kinetics. In the present study, we assessed the association between the ABCC2 −24C>T polymorphism and methotrexate (MTX) toxicities in childhood ALL patients treated with high-dose MTX. A total of 112 Han Chinese ALL patients were treated with high-dose MTX according to the ALL-Berlin-Frankfurt-Muenster 2000 protocol. Our results showed that presence of the −24T allele in ABCC2 gene led to significantly higher MTX plasma concentrations at 48 hours after the start of infusion, which would strengthen over repeated MTX infusion. The −24T allele in ABCC2 gene was significantly associated with higher risks of high-grade hematologic (leucopenia, anemia, and thrombocytopenia) and non-hematologic (gastrointestinal and mucosal damage/oral mucositis) MTX toxicities. This study provides the first evidence that the −24T allele in ABCC2 gene is associated with the severity of MTX toxicities, which add fresh insights into clinical application of high-dose MTX and individualization of MTX treatment.
登录
查看更多内容
影响因子：
20.3
作者：
Ansari, Marc;Sauty, Geraldine;Krajinovic, Maja
通讯作者：
Krajinovic, Maja
影响因子：
20.3
作者：
Ramsey, Laura B.;Panetta, John C.;Relling, Mary V.
通讯作者：
Relling, Mary V.
影响因子：
2.6
作者：
Lopez-Lopez, Elixabet;Ballesteros, Javier;Garcia-Orad, Africa
通讯作者：
Garcia-Orad, Africa
影响因子：
1.8
作者：
Zhang, W. -X.;Chen, B.;Cai, W.
通讯作者：
Cai, W.
DOI：
10.1016/j.ijrobp.2012.10.021
发表时间：
2013-03-01
影响因子：
7
作者：
Dragun, Anthony E.;Quillo, Amy R.;Spanos, William J.
通讯作者：
Spanos, William J.