权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Combination Strategies for Anthracycline Cardiotoxicity

蒽环类药物心脏毒性的联合治疗策略

基本信息

批准号：
7272920
负责人：
John Anthony Bauer
金额：
$ 18.52万
依托单位：
NOVA-THER TECHNOLOGIES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7272920
关键词：
Address Adult Anthracycline Antibiotics Anthracyclines Antineoplastic Agents Apoptosis Area Ascites Biology Blood Chemical Analysis Breast Cancer Model Businesses Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular system Cells Chemistry Chemotherapy-Oncologic Procedure Child Childhood Childhood Leukemia Class Clinical Clinical Treatment Consensus Development Dexrazoxane Dose Dose-Limiting Doxorubicin End Point Functional disorder Goals Heart Neoplasms Histopathology Impairment In Situ In Vitro Infusion procedures Injury Iron Left Ventricular Dysfunction Light Liquid substance MCF7 cell Malignant Neoplasms Marketing Measurement Mediating Metabolism Modeling Mus Myocardial Myocardium NOS2A gene Nitric Oxide Nitrogen Oxidants Oxygen Performance Peroxonitrite Pharmaceutical Preparations Phase Phase I Clinical Trials Prevention Prevention strategy Range Reaction Reactive Nitrogen Species Reporting Research Research Personnel Rodent Model Safety Solid Neoplasm Solutions Superoxides System Testing Text Therapeutic Therapeutic Uses Time Tissues Toxic effect Treatment Protocols Tumor Tissue United States Food and Drug Administration Zinecard base cancer cell cancer pharmacology cell injury cell killing chemotherapy clinical efficacy concept design human NOS2A protein in vivo innovation leukemia leukemia/lymphoma malignant breast neoplasm mouse model pre-clinical research and development research study tumor tumor progression

项目摘要

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).

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）。