Contribution of CBRs and AKRs to the Pharmacodynamics of Anthracycline Drugs

描述(由申请人提供)：在一些患者中，使用蒽环类药物进行癌症化疗与心脏毒性的发展有关。蒽环类药物心脏毒性的发病机制部分是由心脏毒性酒精代谢物(如柔红霉素)的心脏内合成所介导的。多形羰基还原酶(CBRs)和醛酮还原酶(AKRs)可合成蒽环类乙醇代谢产物。我们的研究有助于：1)确定CBR基因中影响蒽环类药物药效的变异，2)确定调控CBRs表达的转录因子和microRNAs，3)记录特定AKR和CBRs在肝脏和心脏--蒽环类药物药效的关键器官--表达和活性的个体间差异程度，以及4)确定CBR基因多态对儿科癌症幸存者与蒽环类药物相关的心脏毒性风险的贡献。我们的 最近的发现表明：1)DNA甲基化状态影响心脏AKR7A2的表达；2)CBR1、AKR1A1和AKR7A2的蛋白水平是心脏中合成心脏毒性蒽环类酒精代谢物的重要决定因素。然而，30%到50%的心脏内柔红霉素合成率的差异仍然不能用基于组平均的当前线性模型来解释，该模型对个体CBRS/AKRs表达谱之间的差异不敏感，也没有纳入功能性遗传和表观遗传因素。这些基本的局限性阻碍了预测工具的开发，以确定可能发生与蒽环类药物相关的心脏毒性的患者。因此，目标1的研究将确定CBR1、CBR3、AKR1A1、AKR1C3和AKR7A2基因的DNA甲基化状态是否会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成对的外周血淋巴细胞(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CBRS/AKRs的定量遗传、表观遗传学和表型数据，目的是定义特定的表达谱，从而导致心脏毒性代谢物合成的异常值。翻译研究I目标3将确定CBRS和AKR的功能遗传变异是否与通过敏感的组织多普勒应变超声心动图获得的3项心脏毒性测量的变化有关：1)左室射血分数，2)纵向应变，3)径向应变，130名接受阿霉素治疗的乳腺癌患者。同时，我们将确定PBL中阿霉素的最大合成率是否与早期心脏毒性的超声心动图变化有关。这项研究产生的工具可能会被纳入全面的临床算法，目的是识别具有蒽环类药物相关心脏毒性风险的患者。

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.