BACKGROUND & AIMS:
:Doxorubicin (DOX), or Adriamycin, an anthracycline antibiotic discovered serendipitously as a chemotherapeutic drug several decades ago, is still one of the most effective drugs for treating various adult and pediatric cancers (breast cancer, Hodgkin's disease, lymphoblastic leukemia). However, one of the major side effects of the continuous use of DOX is dose-dependent, long-term, and potentially lethal cardiovascular toxicity (congestive heart failure and cardiomyopathy) in cancer survivors many years after cessation of chemotherapy. In addition, predisposition to cardiotoxicity varied considerably among individuals. The long-held notion that DOX cardiotoxicity is caused by reactive oxygen species formed from the redox-cycling of DOX semiquinone lacks rigorous proof in a chronic animal model, and administration of reactive oxygen species detoxifying agents failed to reverse DOX-induced cardiac problems. In this review, I discuss the pros and cons of the reactive oxygen species pathway as a primary or secondary mechanism of DOX cardiotoxicity, the role of topoisomerases, and the potential use of mitochondrial-biogenesis-enhancing compounds in reversing DOX-induced cardiomyopathy. New approaches for well-designed clinical trials that repurpose FDA-approved drugs and naturally occurring polyphenolic compounds prophylactically to prevent or mitigate cardiovascular complications in both pediatric and adult cancer survivors are needed. Essentially, the focus should be on enhancing mitochondrial biogenesis to prevent or mitigate DOX-induced cardiotoxicity.
背景与目标:
: 阿霉素 (DOX) 或阿霉素,几十年前偶然发现的蒽环类抗生素作为化学治疗药物,仍然是治疗各种成人和儿童癌症 (乳腺癌,霍奇金病,淋巴细胞白血病) 的最有效药物之一。然而,持续使用DOX的主要副作用之一是在停止化疗多年后癌症幸存者中剂量依赖性,长期和潜在的致命心血管毒性 (充血性心力衰竭和心肌病)。此外,个体之间对心脏毒性的易感性差异很大。长期以来认为DOX心脏毒性是由DOX半醌的氧化还原循环形成的活性氧引起的观点在慢性动物模型中缺乏严格的证据,并且使用活性氧解毒剂未能逆转DOX引起的心脏问题。在这篇综述中,我讨论了活性氧途径作为DOX心脏毒性的主要或次要机制的利弊,拓扑异构酶的作用以及线粒体生物发生增强化合物在逆转DOX诱导的心肌病中的潜在用途。需要采用新的方法进行精心设计的临床试验,以预防性地使用FDA批准的药物和天然存在的多酚化合物,以预防或减轻小儿和成人癌症幸存者的心血管并发症。从本质上讲,重点应该放在增强线粒体生物发生上,以预防或减轻DOX引起的心脏毒性。