Hershko C, Pinson A, Link G
Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
Acta Haematol. 1996;95(1):87-92. doi: 10.1159/000203954.
The use of anthracycline antineoplastic drugs is limited by a cumulative, dose-dependent toxicity to the heart. Of the cellular organelles proposed as possible primary sites of anthracycline toxicity, the mitochondrial membrane appears to be most likely target. Cardiolipin, a major phospholipid component of the inner mitochondrial membrane is rich in polyunsaturated fatty acids and is particularly susceptible to peroxidative injury by harmful radicals produced by redox cycling of anthracyclines. This, in turn, leads to the inactivation of key enzymes in the mitochondrial respiratory chain. Since the formation of free radicals is catalyzed by iron through the Haber-Weiss reaction, it was hypothesized that iron depletion by deferoxamine (DFO) may limit anthracycline cardiotoxicity. Recent studies indicate that iron-loading aggravates doxorubicin cardiotoxicity by enhancing mitochondrial damage, and this can be prevented by prior DFO treatment. Although these observations are intriguing, further studies are required to show that the cardioprotective effects of DFO do not interfere with the therapeutic, antitumoral action of anthracyclines.
蒽环类抗肿瘤药物的使用受到其对心脏累积性、剂量依赖性毒性的限制。在被认为可能是蒽环类毒性主要原发部位的细胞器中，线粒体膜似乎是最可能的靶点。心磷脂是线粒体内膜的主要磷脂成分，富含多不饱和脂肪酸，特别容易受到蒽环类药物氧化还原循环产生的有害自由基的过氧化损伤。这进而导致线粒体呼吸链中关键酶的失活。由于铁通过哈伯-维伊斯反应催化自由基的形成，因此有人推测去铁胺（DFO）耗竭铁可能会限制蒽环类药物的心脏毒性。最近的研究表明，铁负荷通过加重线粒体损伤而加剧阿霉素的心脏毒性，而这可以通过预先进行DFO治疗来预防。尽管这些观察结果很有趣，但还需要进一步研究以表明DFO的心脏保护作用不会干扰蒽环类药物的治疗性抗肿瘤作用。
