Contribution of CBRs and AKRs to the Pharmacodynamics of Anthracycline Drugs

描述（由申请方提供）：在某些患者中，使用蒽环类药物进行癌症化疗与心脏毒性的发生有关。蒽环类药物相关的心脏毒性的发病机制部分是由心脏毒性醇代谢物的心内合成介导的（例如，柔红霉素）。蒽环醇代谢物由多晶型羰基还原酶（CBR）和醛酮还原酶（AKR）合成。我们的研究有助于：1）鉴定影响蒽环类药物药效学的CBR基因中的变体，2）鉴定调节CBR表达的转录因子和微RNA，3）记录肝脏和心脏（蒽环类药物药效学的关键器官）中特异性AKR和CBR的表达和活性的个体间变异程度，和4）确定CBR中遗传多态性对儿科癌症幸存者中蒽环类药物相关心脏毒性风险的贡献。我们 最近的调查结果表明：1）DNA甲基化状态影响AKR7A2的心脏表达，以及2）CBR1、AKR1A1和AKR7A2的蛋白水平，这是心脏中心脏毒性蒽环类醇代谢物合成的重要决定因素。尽管如此，心内柔红霉素合成率的30%至50%的差异仍然无法通过基于组平均值的当前线性模型来解释，该线性模型对个体CBR/AKR表达谱之间的变化不敏感，并且不包含功能性遗传和表观遗传因素。这些基本的限制阻碍了用于识别可能发展蒽环类药物相关心脏毒性的患者的预测工具的发展。因此，目标1中的研究将确定CBR 1、CBR 3、AKR1A1、AKR1C3和AKR7A2基因中的DNA甲基化状态是否影响心脏和肝脏中心脏毒性代谢物的基因表达和合成。在目标2中，我们将开发新的定量方法来预测心脏和肝脏以及配对外周血淋巴细胞（PBL）中蒽环类代谢物的合成。这些方法将整合参与蒽环类药物代谢的CBR/AKR的定量遗传、表观遗传和表型数据，目的是定义导致心脏毒性代谢物合成异常值的特定表达谱。目的3转化研究将确定CBR和AKR中的功能性遗传变异体是否与通过敏感组织多普勒应变超声心动图获得的3种心脏毒性测量结果的变化相关：1）左心室射血分数，2）纵向应变，和3）径向应变，在130名接受阿霉素治疗的乳腺癌患者中。同时，我们将确定PBL中多柔比星的最大合成率是否与超声心动图变化相关，提示早期心脏毒性。从这项研究中产生的工具可能会被纳入全面的临床算法，目的是确定患者的蒽环类药物相关的心脏毒性的风险。

DESCRIPTION (provided by applicant): The use of anthracyclines for cancer chemotherapy is associated with the development of cardiotoxicity in some patients. The pathogenesis of anthracycline-related cardiotoxicity is mediated in part by the intracardiac synthesis of cardiotoxic alcohol metabolites (e.g., daunorubicinol). Anthracycline alcohol metabolites are synthesized by polymorphic carbonyl reductases (CBRs) and aldo-keto reductases (AKRs). Our research has contributed to: 1) identifying variants in CBR genes that impact the pharmacodynamics of anthracyclines, 2) identifying transcription factors and microRNAs that regulate the expression of CBRs, 3) documenting the extent of interindividual variability in the expression and activity of specific AKRs and CBRs in liver and heart, key organs for the pharmacodynamics of anthracyclines, and 4) defining the contribution of genetic polymorphisms in CBRs to the risk for anthracycline-related cardiotoxicity in survivors of pediatric cancers. Our recent findings indicate that: 1) DNA methylation status impacts cardiac expression of AKR7A2, and 2) protein levels of CBR1, AKR1A1, and AKR7A2, which are important determinants for the synthesis of cardiotoxic anthracycline alcohol metabolites in heart. Nonetheless, 30% to 50% of the variance in intracardiac daunorubicinol synthesis rates remains unexplained by current linear models based on group averages, which are insensitive to variation between individual CBRs/AKRs expression profiles and do not incorporate functional genetic and epigenetic factors. These fundamental limitations hamper the development of predictive tools for identifying patients likely to develop anthracycline-related cardiotoxicity. Thus, studies in Aim 1 will determine whether DNA methylation status in CBR1, CBR3, AKR1A1, AKR1C3, and AKR7A2 genes impacts gene expression and synthesis of cardiotoxic metabolites in heart and liver. In Aim 2, we will develop novel quantitative methods to predict the synthesis of anthracycline metabolites in heart and liver, and in paired peripheral blood lymphocytes (PBL). These methods will integrate quantitative genetic, epigenetic, and phenotypic data for the CBRs/AKRs involved in the metabolism of anthracyclines with the aim of defining specific expression profiles that result in outlier values for the synthesis of cardiotoxic metabolites. Translational studies i Aim 3 will determine whether functional genetic variants in the CBRs and AKRs are associated with changes in 3 measurements of cardiotoxicity obtained by sensitive tissue Doppler strain echocardiography: 1) left ventricular ejection fraction, 2) longitudinal strain, and 3) radial stran, in 130 breast cancer patients undergoing treatment with doxorubicin. In parallel, we will determine whether doxorubicinol maximal synthesis rates in PBL are associated with echocardiographic changes indicative of early cardiotoxicity. The tools arising from this research can potentially be incorporated into comprehensive clinical algorithms with the aim of identifying patients at risk for anthracycline-related cardiotoxicity.