A High Throughput Assay for Cancer Drug Cardiotoxicity

癌症药物心脏毒性的高通量测定

• 批准号: 6743535
• 负责人: ECKHARD K FICKER
• 金额: $ 24.88万
• 依托单位: CHANXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-19 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6743535
• 关键词: antibody; antineoplastics; bioassay; bioluminescence; biotechnology; cardiotoxin; drug interactions; drug screening /evaluation; electrocardiography; high throughput technology; intracellular transport; ion channel blocker; laboratory rabbit; membrane channels; membrane transport proteins; method development; protein localization; therapy adverse effect; voltage /patch clamp; western blottings

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.

描述（由申请人提供）： 该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，越来越多的不良心脏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，用于治疗复发性或难治性急性早幼粒细胞白血病。三氧化二砷导致QT间期延长和尖端扭转型室性心动过速。认识到抗癌药物对心脏的损害是很重要的，这样（1）可以仔细监测患者的ECG变化，（2）可以避免电解质失衡和与其他药物的不良相互作用，（3）可以考虑替代治疗策略。心脏钾通道hERG是不必要的药物相互作用的常见靶点，通常导致患者获得性长QT综合征。这是经常，但不总是，由于急性通道阻滞。我们已经发现，hERG的细胞表面表达显着降低暴露于目前正在进行临床试验的抗癌药物，格尔德霉素和根赤霉素的分子伴侣Hsp 90的两种抑制剂。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滞产生心脏毒性副作用，而且可能通过损害心脏离子通道和转运蛋白的生物合成和运输产生心脏毒性副作用。本提案的具体目的是：1）开发一种用于评价抗癌化合物的心脏易感性的高通量方法，并建立我们的方法用于主要复极化心脏电流的原理证明; 2）将该方法扩展到有助于心脏复极化的其他离子通道和转运蛋白。