Combination Strategies for Anthracycline Cardiotoxicity

说明(申请人提供)：尽管阿霉素(DOX)被广泛使用，但其临床应用受到剂量限制的心脏毒性的影响。目前批准的治疗方法(右拉唑烷)在成人中只有适度的价值，它在儿童心脏保护中的有效性仍在调查中。在Dexrazoxane联合给药期间，DOX的疗效似乎也降低了；这种对心肌缺乏选择性保护的情况阻碍了其临床应用。我们首次证明了在DOX心肌病期间心脏形成过氧亚硝酸盐、NOS2的诱导以及对心肌细胞代谢/能量学关键成分的氧化损伤。我们已经确定了一种在体外对心肌细胞提供显著保护而对DOX诱导的癌细胞杀伤没有影响的药物混合物。它们的每一种成分都是安全的，它们的组合提供了独特的保护价值。我们将使用两个与DOX临床应用相关的已建立的可靠的啮齿动物癌症模型(乳腺癌模型和白血病模型)在体内测试这种方法。我们的目标是：(1)在小鼠身上评价已识别的输液的安全性，并在体内证明对DOX引起的心功能障碍的保护作用；(2)在乳腺癌进展的小鼠模型中证明选择性心脏保护而不影响DOX的杀瘤作用的原则；(3)在儿童白血病的体内模型中证明选择性心肌保护的作用。第一阶段的终点包括展示一种安全的输液溶液，该溶液可以在不损害体内DOX杀瘤作用的情况下，为心脏组织提供针对DOX损伤和功能障碍的特定保护。尽管阿霉素(DOX)被广泛使用，但其临床效用受到剂量限制的心脏毒性的影响，而目前批准的治疗方法(Dexrazoxane)在成人中只有适度的价值，其在儿童心脏保护中的有效性仍在调查中。我们已经确定了一种在体外对心肌细胞提供显著保护而对DOX诱导的癌细胞杀伤没有影响的药物混合物。我们将使用两个与DOX临床应用相关的已建立的可靠的啮齿动物癌症模型(乳腺癌模型和白血病模型)在体内测试这种方法。

DESCRIPTION (provided by applicant): Despite its widespread use, the clinical utility of doxorubicin (DOX) is specifically compromised by dose-limiting cardiotoxicities. Currently approved therapy (dexrazoxane) has only modest value in adults and its usefulness in children for cardiac protection is still being investigated. Efficacy of DOX also seems to be reduced during dexrazoxane co-administration; this lack of selective protection of heart muscle discourages its clinical use. We have demonstrated first-time evidence of cardiac formation of peroxynitrite, NOS2 induction, and oxidative injury to key components of cardiomyocyte metabolism/energetics during DOX cardiomyopathy. We have identified a mixture of agents that provided remarkable protection of cardiac myocytes in vitro with no effect on DOX induced cancer cell killing. Their components are each known to be safe, and their combination provided unique protective value. We will test this approach in vivo, using two established and reliable rodent models of cancer relevant to DOX clinical use (breast cancer model and leukemia models). Our AIMS are: (1) Evaluate the safety of the identified infusion solution in mice and demonstrate protection from DOX induced cardiac dysfunction in vivo; (2) Demonstrate proof of principle for selective cardioprotection with no effect on DOX tumoricidal actions in a mouse model of breast cancer tumor progression; (3) Demonstrate selective effects for myocardial protection in an in vivo mouse model of childhood leukemia. Phase I endpoints include the demonstration of a safe infusion solution that provides specific protection of cardiac tissue from DOX injury and dysfunction without impairing DOX tumoricidal actions in vivo. Despite its widespread use, the clinical utility of doxorubicin (DOX) is specifically compromised by dose-limiting cardiotoxicities while currently approved therapy (dexrazoxane) has only modest value in adults and its usefulness in children for cardiac protection is still being investigated. We have identified a mixture of agents that provided remarkable protection of cardiac myocytes in vitro with no effect on DOX induced cancer cell killing. We will test this approach in vivo, using two established and reliable rodent models of cancer relevant to DOX clinical use (breast cancer model and leukemia models).