药物转运体OCTN2表达和DNA甲基化影响伊马替尼对CML疗效的药物基因组学研究

Imatinib is a targeted inhibitor for tyrosine kinases, and is firstly approved for the treatment of chronic myeloid leukemia (CML).The research of imatinib found multiple biomarkers related with the therapeutic effect, drug resistance and adverse reaction of imatinib in pharmacogenetics. Our previous studies found that transporter OCTN2 effectively uptake imatinib, and its expression was correlated with the sensitivity of imatinib. Differential expression of OCTN2 in the CML patients was negatively related with methylated extent of promoter. Based on the previous research, this study will investigate the effect of expression of OCTN2 in CML and the regulation of methylation promoter on the pharmacokinetics, therapeutic effect and toxicity of imatinib from the aspects of molecular cell biology, animal and clinical levels. It is benifical for the investigation of OCTN2 and multiple genes as pharmacogenomic biomarkers directing clinical personalized medicine of imatinib.

伊马替尼是首个用于基因靶向治疗慢性髓性白血病（CML）的酪氨酸激酶抑制剂。伊马替尼的遗传药理学研究发现包括药物靶点、药物代谢酶和药物转运体的多种生物标志物与伊马替尼疗效、耐药和不良反应相关。本课题组前期研究发现，药物转运体OCTN2能高效转运伊马替尼，且OCTN2表达量与伊马替尼敏感性密切相关。在CML患者中OCTN2的差异性表达与其启动子甲基化程度存在负相关。本研究拟在前期研究基础上，从分子、细胞、动物和临床水平探讨CML中OCTN2表达与启动子甲基化调控对伊马替尼药代动力学、疗效、毒性等方面的影响。研究将有助于考察OCTN2及多基因组合作为药物基因组标志物指导伊马替尼临床个体化用药。

伊马替尼是首个用于基因靶向治疗慢性髓性白血病（CML）的酪氨酸激酶抑制剂。伊.马替尼的遗传药理学研究发现包括药物靶点、药物代谢酶和药物转运体的多种生物标志物.与伊马替尼疗效、耐药和不良反应相关。本课题组前期研究发现，药物转运体OCTN2能高.效转运伊马替尼，且OCTN2表达量与伊马替尼敏感性密切相关。在CML患者中OCTN2的差异.性表达与其启动子甲基化程度存在负相关。本研究拟在前期研究基础上，从分子、细胞、.动物和临床水平探讨CML中OCTN2表达与启动子甲基化调控对伊马替尼药代动力学、疗效、.毒性等方面的影响。研究将有助于考察OCTN2及多基因组合作为药物基因组标志物指导伊.马替尼临床个体化用药。