Combination Strategies for Anthracycline Cardiotoxicity

描述（由申请人提供）：尽管多柔比星（DOX）被广泛使用，但其临床应用受到剂量限制性心脏毒性的损害。目前批准的治疗（dexrazoxane）在成人中仅具有中等价值，其对儿童心脏保护的有效性仍在研究中。dexrazoxane合用时，DOX的疗效似乎也会降低；心肌缺乏选择性保护阻碍了其临床应用。我们首次证明了DOX心肌病期间心肌细胞代谢/能量学关键成分的过氧化亚硝酸盐形成、NOS2诱导和氧化损伤的证据。我们已经确定了一种混合物，在体外对心肌细胞提供显著的保护，而对DOX诱导的癌细胞杀伤没有影响。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。我们将在体内测试这种方法，使用两种与DOX临床应用相关的已建立且可靠的啮齿动物癌症模型（乳腺癌模型和白血病模型）。我们的目的是：(1)评估所鉴定的输注液在小鼠体内的安全性，并证明对DOX诱导的心功能障碍的保护作用；(2)在乳腺癌肿瘤进展的小鼠模型中证明选择性心脏保护的原理，而不影响DOX的杀瘤作用；(3)在儿童白血病小鼠体内模型中证明心肌保护的选择性作用。I期终点包括证明一种安全的输注溶液，可以在不损害DOX体内杀肿瘤作用的情况下，对心脏组织提供特异性保护，免受DOX损伤和功能障碍。尽管多柔比星（DOX）被广泛使用，但其临床应用受到剂量限制性心脏毒性的影响，而目前批准的治疗（右拉唑烷）在成人中仅具有中等价值，其对儿童心脏保护的有效性仍在研究中。我们已经确定了一种混合物，在体外对心肌细胞提供显著的保护，而对DOX诱导的癌细胞杀伤没有影响。我们将在体内测试这种方法，使用两种与DOX临床应用相关的已建立且可靠的啮齿动物癌症模型（乳腺癌模型和白血病模型）。

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).