Anthracycline Specificities of Carbonyl Reductases

羰基还原酶的蒽环类特异性

• 批准号: 6670083
• 负责人: Henry Charlier
• 金额: $ 13.07万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6670083
• 关键词: SDS polyacrylamide gel electrophoresis; animal tissue; anthracyclines; antineoplastics; carbonyl compound; catalyst; cytoplasm; cytotoxicity; daunorubicin; disease /disorder model; doxorubicin; enzyme activity; enzyme mechanism; enzyme substrate; model design /development; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; thin layer chromatography

DESCRIPTION (provided by applicant): Anthracyclines, such as doxorubicin and daunorubicin, are a family of drugs commonly used to treat cancer. Though anthracyclines are potent anti-tumor drugs, their use is limited, as they also are known to be toxic to the heart and have the potential to cause congestive heart failure in many of the patients. There is accumulating evidence that the toxic effects on the heart are largely attributable to an anthracycline metabolite that is formed and retained in cardiac cells. The conversion of the anthracyclines to their cardiotoxic metabolites is catalyzed by carbonyl reductase. Preliminary studies with rabbit heart have uncovered several different carbonyl reductases, each with different catalytic efficiencies for daunorubicin and doxorubicin. This important finding may help explain why, in anthracycline cardiotoxicity studies (using doxorubicin) performed with rabbits, only 50 percent of the rabbits developed cardiotoxicity. It is hypothesized that the rabbits with high sensitivity to the doxorubicin possessed a complement of enzymes that had good activity on doxorubicin, while those that did not develop cardiotoxicity did not possess such enzymes. More work is needed to further test this hypothesis. The specific aims of this project focus on the purification (Specific Aim 1) and kinetic analysis (Specific Aim 2) of the enzymes with anthracycline reductase activity present in rabbit heart. This project will be a prelude to future studies aimed at correlating the distribution of anthracycline reductases with resistance (or susceptibility) to cardiotoxicity. The long-term goal of this study is to be able to develop a rabbit model for predicting likelihood of cardiotoxicity as a function of the anthracycline reductases that the rabbits possess. Ultimately such a model could be extended to humans, and as a result, patients could be assessed for risk of developing cardiotoxicity by determining the complement of anthracycline reductases that they possess. The information from this proposal may be used to improve the use of anthracyclines in the treatment of cancer by leading to treatments that greatly reduce the threat of heart damage.

描述（由申请人提供）： 蒽环类药物，如阿霉素和柔红霉素，是常用于治疗癌症的药物家族。虽然蒽环类药物是有效的抗肿瘤药物，但它们的使用是有限的，因为它们也被认为对心脏有毒，并有可能导致许多患者的充血性心力衰竭。 越来越多的证据表明，对心脏的毒性作用主要归因于在心脏细胞中形成和保留的蒽环类代谢物。蒽环类药物转化为心脏毒性代谢物是由羰基还原酶催化的。对兔心脏的初步研究发现了几种不同的羰基还原酶，每种对柔红霉素和阿霉素具有不同的催化效率。这一重要发现可能有助于解释为什么在对兔子进行的蒽环类药物心脏毒性研究（使用阿霉素）中，只有50%的兔子出现心脏毒性。假设对阿霉素具有高敏感性的兔子具有对阿霉素具有良好活性的酶的补充，而那些没有发生心脏毒性的兔子没有这种酶。需要做更多的工作来进一步检验这一假设。本项目的具体目标集中在纯化（具体目标1）和动力学分析（具体目标2）的酶与蒽环还原酶活性存在于兔心脏。该项目将是未来研究的前奏，旨在将蒽环类还原酶的分布与心脏毒性的抗性（或敏感性）相关联。本研究的长期目标是能够开发一种兔模型，用于预测兔所具有的蒽环类还原酶的心脏毒性可能性。最终，这种模型可以扩展到人类，因此，可以通过确定患者所拥有的蒽环类还原酶的补体来评估患者发生心脏毒性的风险。该提案中的信息可用于改善蒽环类药物在癌症治疗中的使用，从而大大降低心脏损伤的威胁。