ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis
ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis
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DOI：
10.1093/brain/awp164
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发表时间：
2009-09-01
期刊：
影响因子：
14.5
通讯作者：
Chan, A.
中科院分区：
文献类型：
--
作者：
Cotte, S.;von Ahsen, N.;Chan, A.
米托蒽醌（MX）在高活性多发性硬化症中的升级治疗受到部分剂量依赖性副作用的限制。治疗反应的预测因素可能导致个体化风险分层和MX剂量。atp结合的卡带转运体ABCB1和ABCG2代表了活跃细胞MX外流中涉及的多药耐药机制。在这里，我们研究了abc基因单核苷酸多态性（snp）在临床MX反应中的作用，并通过体外和体内实验数据得到证实。分析了832例多发性硬化症患者（德国、西班牙）和264例健康供者中ABCB1 2677GT、3435CT和5个abcg2 - snp的频率。利用基于流式细胞术的体外实验，两种abc基因变异等位基因（指定基因型ABCB1/ABCG2-L（低），22.2例患者）的白细胞MX外排比普通等位基因纯合的个体（ABCB1/ABCG2-H（高），p0.05, 14.8例患者）的白细胞MX外排低37.7%，导致基因型依赖性MX积累和细胞死亡。体外添加糖皮质激素（GCs）可抑制MX外排。abc转运蛋白在白细胞亚群、胶质细胞和神经元细胞以及心肌（即可能受MX治疗影响的细胞/组织）中高度表达。在Abcg2（/）动物的实验性自身免疫性脑脊髓炎中进一步证实了体内意义。使用在野生型动物中无效的MX剂量，Abcg2（/）小鼠的病程和组织病理学得到了明显改善。对MX单药治疗患者（155例）进行回顾性临床分析，以扩大残疾状态量表、复发率和多发性硬化功能复合指标为主要结局参数。与ABCB1/ abcg2功能降低相关的基因型患者的临床缓解率[155例患者中总121例（78.1例）]显著升高[ABCB1/ABCG2-H应答者15/24（62.5例），ABCB1/ABCG2-I应答者78/98（79.6例），ABCB1/ABCG2-L应答者28/33（84.8例），精确cochrana - armitage检验P = 0.039]。随着ABCB1/ABCG2评分的增加（从ABCB1/ABCG2- h到I-，从I到L），应答的优势比为1.9 （95 CI 1.03.5）。在36例有严重心脏或血液副作用的患者中，基因型频率无统计学意义上的相关差异。然而，一名活检患者仅在24 mg/m(2) MX后才证实心肌病，表现出一种罕见的基因型，3个abc转运基因中存在变异的部分纯合等位基因。总之，abc转运体基因的snp可能作为与多发性硬化症患者MX治疗的临床反应相关的药理学标记。MX/ gc联合处理值得进一步研究。
Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677GT, 3435CT and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2 of patients) was 37.7 lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P 0.05, 14.8 of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2(/) animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2(/) mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6), ABCB1/ABCG2-L 28/33 (84.8), exact Cochran-Armitage test P 0.039]. The odds ratio for response was 1.9 (95 CI 1.03.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to I-, and I to L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m(2) MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation.