Anthracycline Specificities of Carbonyl Reductases

描述(由申请人提供)： 蒽环类药物，如阿霉素和柔红霉素，是一类通常用于治疗癌症的药物。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害，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，对心脏的毒性作用在很大程度上可归因于一种在心肌细胞中形成并保留的蒽环类代谢物。这些蒽环类化合物转化为心脏毒性代谢物的过程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，每种酶对柔红霉素和阿霉素具有不同的催化效率。这一重要的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。据推测，对阿霉素高度敏感的兔子具有对阿霉素具有良好活性的酶的补充物，而那些没有出现心脏毒性的兔子则没有这种酶。还需要更多的工作来进一步检验这一假说。本项目的具体目标是纯化(特异性目标1)和动力学分析(特异性目标2)在兔心脏中存在的具有蒽环素还原酶活性的酶。该项目将是未来旨在将蒽环类还原酶的分布与心脏毒性耐药性(或敏感性)相关联的研究的前奏。这项研究的长期目标是能够建立一种兔模型，以预测由于兔所具有的蒽环类还原酶而发生心脏毒性的可能性。最终，这样的模型可以扩展到人类，结果是，可以通过确定患者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。这项提案中的信息可能被用来通过导致极大地减少心脏损伤威胁的治疗来改善蒽环类药物在癌症治疗中的使用。

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.