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，但其临床效用特别受到剂量限制性心脏毒性的影响。目前批准的治疗（右雷佐生）在成人中仅具有适度的价值，其在儿童中的心脏保护作用仍在研究中。在右雷佐生联合给药期间，DOX的疗效似乎也降低;这种缺乏心肌选择性保护的情况阻碍了其临床应用。我们已经证明了第一时间的证据，心脏形成过氧亚硝酸盐，NOS 2诱导，氧化损伤的关键组成部分，心肌细胞代谢/能量在DOX心肌病。我们已经鉴定了在体外提供对心肌细胞的显著保护而对DOX诱导的癌细胞杀伤没有影响的试剂的混合物。它们的成分都是安全的，它们的组合提供了独特的保护价值。我们将使用两种与DOX临床使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）在体内测试这种方法。我们的目标是：（1）评价所鉴定的输注溶液在小鼠中的安全性，并证明在体内对DOX诱导的心功能障碍的保护作用;（2）证明在乳腺癌肿瘤进展的小鼠模型中对DOX杀肿瘤作用没有影响的选择性心脏保护作用的原理证明;（3）证明在儿童白血病的体内小鼠模型中对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，该溶液提供特异性保护心脏组织免受DOX损伤和功能障碍，而不损害DOX体内杀肿瘤作用。尽管多柔比星（DOX）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（右雷佐生）在成人中仅具有适度的价值，其在儿童中的心脏保护作用仍在研究中。我们已经鉴定了在体外提供对心肌细胞的显著保护而对DOX诱导的癌细胞杀伤没有影响的试剂的混合物。我们将使用两种与DOX临床使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）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).