GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study
GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study
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DOI：
10.18632/oncotarget.20310
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发表时间：
2017-10-31
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影响因子：
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通讯作者：
Krajinovic, Maja
中科院分区：
文献类型：
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作者：
Ansari, Marc;Curtis, Patricia Huezo-Diaz;Krajinovic, Maja
在治疗药物监测后调整白消安（BU）剂量有助于改善造血干细胞移植（HSCT）的结局。通过基因型指导的BU剂量调整可实现进一步改善。为了调查这方面，谷胱甘肽S转移酶基因内的多态性进行了评估。特别是，谷胱甘肽S转移酶A1（GSTA 1）的启动子单倍型在体外进行了评价，报告基因测定和临床，在儿科多中心研究（N = 138）通过与BU药代动力学（PK）和临床结局的关联。启动子活性在GSTA 1单倍型之间显著不同（p< 0.001），支持它们在捕获PK变异性中的重要性。区分了与清除率显著相关（p= 0.009）的四个GSTA 1二倍型组。快代谢能力和慢代谢能力的基础二倍体分别显示较高和较低的BU清除率（ml/min/kg）。具有慢代谢能力的GSTA 1二倍型与窦阻塞综合征、急性移植物抗宿主病和联合治疗相关毒性的较高发生率相关（p< 0.0005）。在研究的其他GST基因中，GSTP 1313 GG与1- 4级急性移植物抗宿主病相关（p= 0.01），GSTM 1非无效基因型与出血性膀胱炎相关（p= 0.003）。本研究进一步强化了GST双倍型/基因型可纳入现有群体药代动力学模型以改善首次BU剂量预测和HSCT结局的假设。
Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N = 138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p< 0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p= 0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment- related toxicity (p< 0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1- 4 (p= 0.01) and GSTM1 non- null genotype was associated with hemorrhagic cystitis (p= 0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes.