A High Throughput Assay for Cancer Drug Cardiotoxicity

描述(由申请人提供)： 这项研究的主要目标是开发一种新的高通量方法来评估抗癌药物的心脏易感性。近年来，越来越多的心脏不良事件与非心脏药物的使用有关。与此相关的抗癌药物的一个重要例子是三氧化二砷，用于治疗复发或难治性急性早幼粒细胞白血病。三氧化二砷可引起QT延长和尖端扭动。重要的是要认识到抗癌药物的心脏易感性，以便(1)可以仔细监测患者的心电图变化，(2)可以避免电解质失衡和与其他药物的不利相互作用，以及(3)可以考虑替代治疗策略。心肌钾通道HERG是有害药物相互作用的常见靶点，经常导致患者获得性长QT综合征。这通常是由于急性通道阻塞，但并不总是如此。我们发现，目前正在进行临床试验的两种伴侣蛋白Hsp90的抑制剂格尔达那霉素和自由基可以显著降低HERG在细胞表面的表达。这两种药物都不是急性HERG阻滞剂。我们认为，治疗药物不仅可能通过急性通道阻断产生心脏毒性副作用，还可能通过影响心脏离子通道和转运体的生物合成和运输而产生副作用。这项建议的具体目的是：1)开发一种高通量的方法来评估抗癌化合物的心脏易感性，并建立我们的方法对主要的复极化心脏电流的原理证明；以及2)将该方法扩展到其他有助于心脏复极的离子通道和转运体。

DESCRIPTION (provided by applicant): The major goal of the proposed research is to develop a novel high throughput method for evaluating the cardiac liability of anticancer drugs. In recent years, more and more adverse cardiac events have been linked to the use of non-cardiac drugs. An important example of an anticancer drug with this association is arsenic trioxide, used for the treatment of relapsed or refractory acute promyelocytic leukemia. Arsenic trioxide causes QT prolongation and torsade de pointes. It is important that the cardiac liability of anticancer drugs be recognized so that (1) patients can be carefully monitored for ECG changes, (2) electrolyte imbalances and unfavorable interactions with other medications can be avoided, and (3) alternative treatment strategies can be considered. The cardiac potassium channel hERG is a frequent target of unwanted drug interactions, often leading to acquired long QT syndrome in patients. This is often, but not always, due to acute channel block. We have found that the cell surface expression of hERG is significantly reduced by exposure to two inhibitors of the chaperone Hsp90 that are currently undergoing clinical trials as anticancer drugs, geldanamycin and radicicol. Neither drug is an acute hERG blocker. We propose that therapeutic drugs may not only produce cardiotoxic side effects by acute channel block but also by compromising the biosynthesis and trafficking of cardiac ion channels and transporters. The specific aims of this proposal are to: 1) develop a high throughput method for evaluating the cardiac liability of anticancer compounds and establish proof of principle of our method for a major repolarizing cardiac current; and 2) extend the method to other ion channels and transporters that contribute to cardiac repolarization.