Exercise and the Attenuation of Chronic Doxorubicin Cardiotoxicity

运动和减轻阿霉素慢性心脏毒性

• 批准号: 7293981
• 负责人: REID HAYWARD
• 金额: $ 16.69万
• 依托单位: UNIVERSITY OF NORTHERN COLORADO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7293981
• 关键词: Acute; Address; Adult; Adverse effects; Aftercare; Animal Model; Anthracycline Antibiotics; Anthracyclines; Antineoplastic Agents; Antioxidants; Apoptosis; Apoptotic; Attenuated; Cancer Patient; Cancer Survivor; Cardiac; Cardiotoxicity; Cardiovascular system; Chelating Agents; Child; Chronic; Clinic; Clinical; Complementary therapies; Development; Dose; Doxorubicin; Echocardiography; Epirubicin; Event; Exercise; Exposure to; Functional disorder; Goals; Health Benefit; Heart; Heart failure; Idarubicin; Individual; Infusion procedures; Institutes; Iron; Laboratories; Lead; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Myocardial; Oxidative Stress; Patients; Personal Satisfaction; Pharmaceutical Preparations; Physical activity; Play; Process; Quality of life; Rate; Rattus; Recording of previous events; Relative (related person); Role; Series; Solid Neoplasm; Specific qualifier value; Time; Toxic effect; Training; Translating; Treatment Protocols; Week; Work; analog; attenuation; cancer rehabilitation; cancer therapy; chemotherapy; day; improved; novel; prevent; programs; research study; response

DESCRIPTION (provided by applicant): Doxorubicin (DOX) is one of the most potent antineoplastic agents used in the treatment of lymphoid malignancies and solid tumors in both adults and children. However, its clinical use is limited by a cumulative myocardial toxicity that can eventually lead to heart failure. Specifically, the broad, long-term objective of this project is to determine the effects of exercise on the chronic cardiac dysfunction associated with DOX treatment and investigate mechanisms that may be involved with any exercise-induced cardioprotection. Three specific aims will provide the framework for this proposal: Specific Aim 1) Determine if exercise training before, during, and after DOX treatment, can attenuate DOX-induced chronic cardiac dysfunction. It has not yet been determined if the beneficial effects of exercise are maintained weeks, or even months, following treatment in animal models. This specific aim will be addressed by allowing rats to voluntarily exercise for 10 weeks, after which they will be treated with DOX (1 mg/kg/day for 10 days) and observed for up to 16 weeks after DOX treatment. During this observation period cardiac function will be periodically assessed using echocardiography and the isolated perfused heart. It is hypothesized that exercise prior to DOX treatment will attenuate DOX cardiotoxicity for up to 16 weeks following DOX treatment. Specific Aim 2) Determine if exercise training during and after DOX treatment can alleviate the chronic cardiac dysfunction that accompanies DOX treatment. Here, a series of experiments is proposed to investigate the effects of exercise training on DOX cardiotoxicity when exercise is initiated at the time DOX treatment begins. In these studies, rats will be allowed to voluntarily exercise beginning the same day a 10-day DOX regimen begins (1 mg/kg/day for 10 days). Cardiac function will be assessed by echocardiography and the isolated perfused heart before and after DOX treatment. It is hypothesized that exercise will be cardioprotective, even when initiated after DOX treatment begins. Specific Aim 3) Investigate the role oxidative stress and apoptosis may play in mediating the beneficial effects, or lack thereof, of exercise on chronic DOX cardiotoxicity. While several mechanisms may be involved, oxidative stress and apoptosis appear to be two means by which DOX cardiotoxicity is mediated. Specific Aim 3 will address the role these processes may play in the cardioprotective effects of exercise. At specified times before and after DOX treatment, hearts will be obtained and analyzed for several markers of oxidative stress and apoptosis. It is hypothesized that exercise training will attenuate the oxidative and apoptotic events associated with DOX. Although improvements in cancer treatment strategies have been witnessed in recent decades, doxorubicin cardiotoxicity remains a clinical dilemma. In order to reap optimal benefits from this drug, it has become necessary to develop complementary therapies that offset DOX cardiotoxicity. We believe that exercise training is a strategy that may provide significant cardiovascular benefits for cancer patients undergoing treatment with doxorubicin. Exercise training in patients undergoing doxorubicin treatment may be able to better tolerate exposure to doxorubicin, or possibly tolerate higher doses of doxorubicin. Such an improved response to doxorubicin treatment may ultimately increase cure rate, long-term survival, and the quality of life for cancer survivors.

描述（由申请人提供）：阿霉素（DOX）是用于治疗成人和儿童淋巴恶性肿瘤和实体瘤的最有效的抗肿瘤剂之一。但是，其临床使用受到累积心肌毒性的限制，最终可能导致心力衰竭。具体而言，该项目的广泛长期目标是确定运动对与DOX治疗相关的慢性心脏功能障碍的影响，并研究可能与任何运动引起的心脏保护有关的机制。三个具体目标将为该提案提供框架：具体目标1）确定在DOX治疗之前，期间和之后是否可以减弱DOX诱导的慢性心脏功能障碍。在动物模型治疗后，尚未确定运动​​的有益效果是否维持数周甚至数月。该特定目标将通过允许大鼠自愿运动10周来解决，之后将用DOX（1 mg/kg/day持续10天）进行治疗，并在DOX治疗后长达16周观察到。在这一观察期间，将使用超声心动图和孤立的灌注心脏进行定期评估心脏功能。假设在DOX治疗之前的运动会减弱DOX治疗后长达16周的DOX心脏毒性。具体目标2）确定在DOX治疗期间和之后的运动训练是否可以减轻DOX治疗伴随的慢性心脏功能障碍。在这里，提出了一系列实验，以研究运动训练对DOX心脏毒性的影响，当时DOX治疗开始了。在这些研究中，将允许大鼠从同一天开始进行10天的DOX方案（1 mg/kg/day 10天）。心脏功能将通过超声心动图和DOX治疗前后的孤立灌注心脏进行评估。可以假设，即使在DOX治疗开始后开始，运动也将是心脏保护。特定目的3）研究氧化应激和凋亡的作用可能在介导慢性DOX心脏毒性的有益作用或缺乏锻炼时起着作用。尽管可能涉及几种机制，但氧化应激和凋亡似乎是介导DOX心脏毒性的两种方法。具体目标3将解决这些过程在运动的心脏保护作用中可能起的作用。在DOX治疗前后的指定时间，将获得心脏并分析几种氧化应激和凋亡的标记。假设运动训练会减轻与DOX相关的氧化和凋亡事件。尽管最近几十年来已经看到了癌症治疗策略的改善，但阿霉素心脏毒性仍然是临床困境。为了从这种药物中获得最佳益处，有必要开发抵消DOX心脏毒性的互补疗法。我们认为，运动训练是一种可能为接受阿霉素治疗的癌症患者提供重大心血管益处的策略。接受阿霉素治疗的患者的运动训练可能能够更好地耐受暴露于阿霉素的接触，或者可能耐受较高剂量的阿霉素。对阿霉素治疗的这种改善的反应最终可以提高治愈率，长期生存以及癌症幸存者的生活质量。