Berthiaume J M, Wallace K B
Toxicology Graduate Program, Medical School, University of Minnesota, Duluth, Minnesota 55812, USA.
Cell Biol Toxicol. 2007 Jan;23(1):15-25. doi: 10.1007/s10565-006-0140-y. Epub 2006 Sep 28.
The anticancer agent Adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity. Numerous studies have attempted to characterize and elucidate the mechanism(s) behind its cardiotoxic effect. Despite a wealth of data covering a wide-range of effects mediated by the drug, the definitive mechanism remains a matter of debate. However, there is consensus that this toxicity is related to the induction of reactive oxygen species (ROS). Induction of ROS in the heart by ADR occurs via redox cycling of the drug at complex I of the electron transport chain. Many studies support the theory that mitochondria are a primary target of ADR-induced oxidative stress, both acutely and long-term. This review focuses on the effects of ADR redox cycling on the mitochondrion, which support the hypothesis that these organelles are indeed a major factor in ADR cardiotoxicity. This review has been constructed with particular emphasis on studies utilizing cardiac models with clinically relevant doses or concentrations of ADR in the hope of advancing our understanding of the mechanisms of ADR toxicity. This compilation of current data may reveal valuable insights for the development of therapeutic strategies better tailored to minimizing the dose-limiting effect of ADR.
抗癌药物阿霉素（ADR）长期以来被认为会引发剂量限制性心脏毒性。众多研究试图描述并阐明其心脏毒性作用背后的机制。尽管有大量数据涵盖了该药物介导的广泛效应，但确切机制仍存在争议。然而，人们一致认为这种毒性与活性氧（ROS）的诱导有关。ADR在心脏中诱导ROS是通过药物在电子传递链复合体I处的氧化还原循环实现的。许多研究支持线粒体是ADR诱导的氧化应激的主要靶点这一理论，无论是在急性还是长期情况下。本综述聚焦于ADR氧化还原循环对线粒体的影响，这些影响支持了这些细胞器确实是ADR心脏毒性主要因素的假说。本综述特别强调了利用具有临床相关剂量或浓度ADR的心脏模型进行的研究，以期增进我们对ADR毒性机制的理解。当前数据的汇总可能会为制定更适合将ADR的剂量限制性效应降至最低的治疗策略提供有价值的见解。
