ANTHRACYCLINE INDUCED CARDIAC TOXICITY: AN IN VITRO MODE

蒽环类药物引起的心脏毒性：体外模式

• 批准号: 3174799
• 负责人: THEODORE J LAMPIDIS
• 金额: $ 12.47万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3174799
• 关键词: DNA repair; anthracyclines; arrhythmia; beta galactosidase; carnitine; chemical structure function; doxorubicin; drug adverse effect; electron microscopy; electron transport; fibroblasts; glycolysis; heart cell; heart contraction; mitochondria; newborn animals; oxidative phosphorylation; selenium; tissue /cell culture; tocopherols; ubiquinone

The dose-dependent cardiomyopathy that develops on chronic administration of adriamycin (ADR), an anthracycline effective in the treatment of a wide variety of human malignancies, severely limits its long-term usage. A number of studies aimed at understanding the cardiopathogenic nature of this drug have been reported. However, the mechanism of cardiotoxicity remains unknown. The aim of this project is to investigate various aspects of our in vitro pulsating cardiac cell system as they relate to ADR cardiotoxicity in man. The uniqueness and importance of an in vitro cardiac cell system is that it provides a sensitive measure of the metabolic effects of drugs on cellular function. The consistency and precision of autorhythmicity of heart cells in culture offers a unique way to investigate these effects. A microscope stage has been designed here to accurately control temperature and pH, two variables to which cardiac cell function is particularly sensitive. An electronic system has been developed which quantitatively records beating patterns. Other techniques that will be used to study the mechanism of toxicity of ADR, ADR analogues (AD 32) and other anti-cancer agents include: Light and electron microscopy, to assess structural damage; RNA and DNA assays, to evaluate synthesis and repair; metabolic inhibitors, as probes for distinguishing between glycolytic and electron transport effects and ATP assays to determine the biochemical effects of these agents. These studies are anticipated to lead to methods of preventing cardiotoxicity.

慢性给药所致的剂量依赖性心肌病 阿霉素(ADR)，一种治疗广泛性黄斑变性的蒽环类药物 多种人类恶性肿瘤，严重限制了其长期使用。一个 旨在了解心脏致病本质的多项研究 据报道，这种药物。然而，心脏毒性的机制 仍然不为人知。这个项目的目的是调查各个方面 我们的体外搏动心脏细胞系统与ADR的关系 对人类的心脏毒性。体外培养的独特性和重要性 心脏细胞系统是它提供了一种敏感的测量 药物对细胞功能的代谢影响。一致性和 培养心肌细胞自律性的精确度提供了一种独特的方法 来研究这些影响。这里已经设计了一个显微镜工作台来 准确控制温度和pH，这两个变量对心肌细胞 功能尤其敏感。一个电子系统已经被 开发了一种定量记录跳动模式的工具。其他技术 这将用于研究ADR、ADR类似物的毒性机制 (公元32)和其他抗癌药物包括：光和电子 显微镜，用于评估结构损伤；RNA和DNA分析，用于评估 合成和修复.作为区分的探针的代谢抑制物 糖酵解和电子传递效应与ATP测定之间的关系 确定这些制剂的生物化学效应。这些研究是 预计将导致预防心脏毒性的方法。