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）：尽管使用了广泛使用，但阿霉素（DOX）的临床实用性被剂量限制的心脏毒性特别损害。目前批准的疗法（Dexrazoxane）在成年人中仅具有适中的价值，并且仍在研究其对儿童对心脏保护的有用性。在右旋唑烷共同给药期间，DOX的功效似乎也降低了。缺乏对心肌的选择性保护会阻止其临床使用。我们已经证明了对多克斯心肌病期间心肌细胞代谢/能量的关键成分的过氧亚硝酸盐，NOS2诱导和氧化性损伤的首次证据。我们已经确定了一种药物的混合物，可在体外对心肌细胞进行明显保护，对DOX诱导的癌细胞杀死没有影响。他们的组件都已安全，它们的组合提供了独特的保护价值。我们将使用与DOX临床使用（乳腺癌模型和白血病模型）相关的两种已建立且可靠的啮齿动物模型来测试这种方法。我们的目的是：（1）评估小鼠中鉴定的输注溶液的安全性，并证明了DOX诱导的体内心脏功能障碍的保护；（2）在乳腺癌肿瘤进展的小鼠模型中，证明了选择性心脏保护的原理证明；（3）在儿童白血病的体内小鼠模型中表现出对心肌保护的选择性作用。第一阶段的终点包括证明安全输液溶液，该溶液可为心脏组织提供特定的保护免受DOX损伤和功能障碍的保护，而不会损害体内DOX肿瘤作用。尽管使用了广泛使用，但阿霉素（DOX）的临床实用性被剂量限制的心脏毒性特别损害，而目前批准的治疗（Dexrazoxane）仅在成人中具有适度的价值，并且其对儿童对心脏保护的有用性仍在研究中。我们已经确定了一种药物的混合物，可在体外对心肌细胞进行明显保护，对DOX诱导的癌细胞杀死没有影响。我们将使用与DOX临床使用（乳腺癌模型和白血病模型）相关的两种已建立且可靠的啮齿动物模型来测试这种方法。