Contribution of CBRs and AKRs to the Pharmacodynamics of Anthracycline Drugs

CBR 和 AKR 对蒽环类药物药效学的贡献

• 批准号: 9043105
• 负责人: Javier Guillermo Blanco
• 金额: $ 30.53万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043105
• 关键词: Acute; Alcohol Oxidoreductases; Alcohols; Algorithms; Anthracyclines; Area; Breast Cancer Patient; Cancer Patient; Cardiac; Cardiomyopathies; Cardiotoxicity; Chemotherapy-Oncologic Procedure; Clinical; Collection; Complex; DNA Methylation; Data; Daunorubicin; Development; Doxorubicin; Duborimycin; Echocardiography; Epigenetic Process; Gene Expression; Genes; Genetic; Genetic Polymorphism; Health; Heart; Human; Incidence; Individual; Left Ventricular Ejection Fraction; Linear Models; Liver; Malignant Childhood Neoplasm; Malignant Neoplasms; Measurement; Mediating; Metabolism; Methods; Methylation; MicroRNAs; Modeling; Molecular Profiling; Morbidity - disease rate; National Institute of General Medical Sciences; Organ; Oxidoreductase; Pathogenesis; Patients; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Promoter Regions; Proteins; Proxy; Quantitative Genetics; Radial; Research; Risk; Sampling; Site; Tissues; Variant; base; chemotherapy; childhood cancer survivor; clinically relevant; defined contribution; gene synthesis; genetic variant; human tissue; insight; interest; novel; peripheral blood; phenotypic data; predictive modeling; predictive tools; prevent; tool; transcription factor; translational study

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.

描述（由申请人提供）：使用蒽环类药物进行癌症化疗与某些患者出现心脏毒性有关。蒽环类药物相关心脏毒性的发病机制部分是由心脏毒性醇代谢物（例如柔红霉素）的心内合成介导的。蒽环醇代谢物由多态性羰基还原酶 (CBR) 和醛酮还原酶 (AKR) 合成。我们的研究有助于：1) 识别影响蒽环类药物药效学的 CBR 基因变异，2) 识别调节 CBR 表达的转录因子和 microRNA，3) 记录肝脏和心脏（蒽环类药物药效学的关键器官）中特定 AKR 和 CBR 的表达和活性的个体间变异程度，以及 4) 定义遗传因素的贡献。 CBR 多态性与儿科癌症幸存者蒽环类药物相关心脏毒性风险的关系。我们的 最近的研究结果表明：1) DNA 甲基化状态影响 AKR7A2 的心脏表达，2) CBR1、AKR1A1 和 AKR7A2 的蛋白水平，它们是心脏毒性蒽环类酒精代谢物合成的重要决定因素。尽管如此，目前基于组平均值的线性模型仍然无法解释心内柔红霉素合成率的 30% 至 50% 的差异，该模型对个体 CBR/AKR 表达谱之间的变化不敏感，并且不包含功能遗传和表观遗传因素。这些基本限制阻碍了用于识别可能发生蒽环类药物相关心脏毒性的患者的预测工具的开发。因此，目标 1 的研究将确定 CBR1、CBR3、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，目的是定义特定的表达谱，从而产生心脏毒性代谢物合成的异常值。转化研究 i 目标 3 将确定 CBR 和 AKR 中的功能性遗传变异是否与敏感组织多普勒应变超声心动图获得的 3 项心脏毒性测量值的变化相关：1) 左心室射血分数，2) 纵向应变，3) 径向应变，研究对象为 130 名接受阿霉素治疗的乳腺癌患者。同时，我们将确定 PBL 中阿霉素最大合成率是否与指示早期心脏毒性的超声心动图变化相关。这项研究产生的工具有可能被纳入综合临床算法中，目的是识别存在蒽环类药物相关心脏毒性风险的患者。