Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia.
Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia.
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DOI：
10.1002/pbc.22845
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发表时间：
2011-03
影响因子：
3.2
通讯作者：
Renbarger, Jamie L.
中科院分区：
文献类型：
--
作者：
Egbelakin, Akinbode;Ferguson, Michael J.;MacGill, Emily A.;Lehmann, Amalia S.;Topletz, Ariel R.;Quinney, Sara K.;Li, Lang;McCammack, Kevin C.;Hall, Stephen D.;Renbarger, Jamie L.
本研究评估细胞色素P450 (CYP) 3A5基因型与长春新碱诱导的儿童前体B细胞急性淋巴细胞白血病（preB ALL）周围神经病变的关系。我们已经在体外证明，CYP3A5比CYP3A4更有效地代谢长春新碱。我们还发现长春新碱神经毒性在非裔美国人（70%表达CYP3A5）中比在白种人中更少见。我们检验了CYP3A5表达者比非CYP3A5表达者经历更少的长春新碱神经病变的假设。这项关于长春新碱神经病变在preB ALL儿童中的药物遗传学研究在印第安纳大学西蒙癌症中心完成。采集全血用于DNA提取和基因分型，同时采集单一时间点的血浆用于长春新碱和初级代谢物（M1）浓度分析。通过图表回顾记录长春新碱神经病变，并根据美国国家癌症研究所不良事件通用术语标准3.0版进行评分。89%的CYP3A5表达者出现神经毒性，而非表达者为100% （p=0.03）。出现神经毒性的治疗月数在表达者和非表达者之间有显著差异（16%比27%，p=0.0007）。有限的药代动力学数据表明，CYP3A5基因型组与非CYP3A5基因型组之间的长春新碱代谢率不同，CYP3A5基因型组的初级代谢物（M1）血浆浓度较高（p=0.0004），而CYP3A5基因型组的代谢比率（[长春新碱]/[M1]）较低（p=0.036）。M1浓度与神经病变严重程度呈负相关（p=0.0316）。在pre - b ALL患儿中，与CYP3A5非表达者相比，CYP3A5表达者较少经历长春新碱诱导的周围神经病变，产生更多的M1，并且代谢率较低。
This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70% express CYP3A5) than in Caucasians. We test the hypothesis that CYP3A5 expressers experience less vincristine neuropathy than do CYP3A5 non-expressers. This study of pharmacogenetics of vincristine neuropathy in children with preB ALL was completed at Indiana University Simon Cancer Center. Whole blood for DNA extraction and genotyping was collected as well as plasma from a single time-point for analysis of vincristine and primary metabolite (M1) concentrations. Vincristine neuropathy was captured via chart review and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. 89% of CYP3A5 expressers experienced neurotoxicity versus 100% of non-expressers (p=0.03). The proportion of treatment months with neurotoxicity was significantly different between the expressers and non-expressers (16% vs. 27%, p=0.0007). Limited pharmacokinetic data suggest different rates of vincristine metabolism between CYP3A5 genotype groups with higher primary metabolite (M1) plasma concentrations (p=0.0004) and lower metabolic ratios ([vincristine]/[M1]) (p=0.036) in the CYP3A5 expressers compared to the CYP3A5 non-expressers. M1 concentration was also inversely related to severity of neuropathy (p=0.0316). In children with preB ALL, CYP3A5 expressers experience less vincristine-induced peripheral neuropathy, produce more M1, and have lower metabolic ratios compared to CYP3A5 non-expressers.
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影响因子：
3.8
作者：
Frost, BM;Lönnerholm, G;de Graaf, SSN
通讯作者：
de Graaf, SSN
影响因子：
30.8
作者：
Kuehl, P;Zhang, J;Schuetz, E
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Schuetz, E
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Cavaletti, G;Jann, S;Giussani, G
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Giussani, G
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Gidding, CEM;Meeuwsen-de Boer, GJ;de Graaf, SSN
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de Graaf, SSN
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CROM, WR;DEGRAAF, SSN;EVANS, WE
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EVANS, WE