Seifert C F, Nesser M E, Thompson D F
Clinical Pharmacy Services, Rapid City Regional Hospital, SD 57701.
Ann Pharmacother. 1994 Sep;28(9):1063-72. doi: 10.1177/106002809402800912.
To review doxorubicin-induced cardiotoxicity and to evaluate the use of dexrazoxane in its prevention.
All animal and human reports involving doxorubicin-induced cardiac adverse effects were searched using MEDLINE combined with a fan search of relevant papers.
Animal, in vitro cellular, and human data are thoroughly reviewed with particular emphasis on doxorubicin-induced cardiotoxicity, including clinical manifestations, risk factors, and mechanisms of toxicity. The role of dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity is reviewed, including mechanism of effect, animal data, and human trials.
Anthracyclines are associated with a cumulative, dose-dependent, irreversible cardiomyopathy that can lead to congestive heart failure and death. The incidence of cardiotoxicity rises sharply at a total lifetime dose of more than 550 mg/m2. Through its semiquinone metabolite, doxorubicin appears to generate superoxide anion and superhydroxide free radicals with iron as a cofactor. Because of poor myocardial concentrations of superoxide dismutase, catalase, and glutathione peroxidase, these free radicals cause extensive lipid peroxidation and mitochondrial destruction.
Dexrazoxane is hydrolyzed to its active form intracellularly and binds iron to prevent the formation of superhydroxide radicals, thus preventing mitochondrial destruction. The effect of dexrazoxane on the prevention of doxorubicin-induced cardiotoxicity is impressive in both animal and human studies. Further research is needed to clearly demonstrate the effect dexrazoxane has on the antitumor effects of combination chemotherapy while defining optimal dosing strategies to minimize myelosuppression and maximize cardioprotection.
回顾多柔比星诱导的心脏毒性，并评估右丙亚胺在预防该毒性中的应用。
使用MEDLINE并结合对相关论文的广泛搜索，检索了所有涉及多柔比星诱导的心脏不良反应的动物和人类报告。
对动物、体外细胞和人类数据进行了全面回顾，特别强调多柔比星诱导的心脏毒性，包括临床表现、危险因素和毒性机制。回顾了右丙亚胺在预防多柔比星诱导的心脏毒性中的作用，包括作用机制、动物数据和人体试验。
蒽环类药物与一种累积性、剂量依赖性、不可逆的心肌病相关，可导致充血性心力衰竭和死亡。当总终身剂量超过550mg/m²时，心脏毒性的发生率急剧上升。多柔比星通过其半醌代谢物，似乎以铁作为辅助因子产生超氧阴离子和超羟基自由基。由于心肌中超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的浓度较低，这些自由基会导致广泛的脂质过氧化和线粒体破坏。
右丙亚胺在细胞内水解为其活性形式，并与铁结合以防止超羟基自由基的形成，从而防止线粒体破坏。在动物和人体研究中，右丙亚胺对预防多柔比星诱导的心脏毒性的效果令人印象深刻。需要进一步研究以明确证明右丙亚胺对联合化疗抗肿瘤效果的影响，同时确定最佳给药策略以尽量减少骨髓抑制并最大化心脏保护作用。
