Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Cancer Chemother Pharmacol. 2010 Jul;66(2):303-14. doi: 10.1007/s00280-009-1164-9. Epub 2009 Nov 14.
The antineoplastic anthracycline doxorubicin can induce a dose-dependent cardiomyopathy that limits the total cumulative dose prescribed to cancer patients. In both preclinical and clinical studies, pretreatment with dexrazoxane, an intracellular iron chelator, partially protects against anthracycline-induced cardiomyopathy. To identify potential additional cardioprotective treatment strategies, we investigated early doxorubicin-induced changes in cardiac gene expression.
Spontaneously hypertensive male rats (n = 47) received weekly intravenous injections of doxorubicin (3 mg/kg) or saline 30 min after pretreatment with dexrazoxane (50 mg/kg) or saline by intraperitoneal injection. Cardiac samples were analyzed 24 h after the first (n = 20), second (n = 13), or third (n = 14) intravenous injection on days 1, 8, or 15 of the study, respectively.
Rats receiving three doses of doxorubicin had minimal myocardial alterations that were attenuated by dexrazoxane. Cardiac expression levels of genes associated with the Nrf2-mediated stress response were increased after a single dose of doxorubicin, but not affected by cardioprotectant pretreatment. In contrast, an early repressive effect of doxorubicin on transcript levels of genes associated with mitochondrial function was attenuated by dexrazoxane pretreatment. Dexrazoxane had little effect on gene expression by itself.
Genomic analysis provided further evidence that mitochondria are the primary target of doxorubicin-induced oxidative damage that leads to cardiomyopathy and the primary site of cardioprotective action by dexrazoxane. Additional strategies that prevent the formation of oxygen radicals by doxorubicin in mitochondria may provide increased cardioprotection.
抗肿瘤蒽环类药物阿霉素可引起剂量依赖性心肌病，从而限制癌症患者的总累积剂量。在临床前和临床研究中，预先使用细胞内铁螯合剂右雷佐生可部分预防蒽环类药物引起的心肌病。为了确定潜在的其他心脏保护治疗策略，我们研究了阿霉素早期诱导的心脏基因表达变化。
自发性高血压雄性大鼠（n = 47）每周接受一次静脉注射阿霉素（3mg/kg），或在预先给予右雷佐生（50mg/kg）30 分钟后给予腹腔内注射生理盐水。在研究的第 1 天、第 8 天或第 15 天，分别在第一次（n = 20）、第二次（n = 13）或第三次（n = 14）静脉注射后 24 小时分析心脏样本。
接受三剂阿霉素的大鼠心肌改变轻微，右雷佐生可减轻这种改变。单次阿霉素给药后，与 Nrf2 介导的应激反应相关的基因表达水平增加，但心脏保护剂预处理对其无影响。相反，右雷佐生预处理可减轻阿霉素对与线粒体功能相关的基因转录水平的早期抑制作用。右雷佐生本身对基因表达影响很小。
基因组分析进一步证明，线粒体是阿霉素诱导的氧化损伤导致心肌病的主要靶点，也是右雷佐生发挥心脏保护作用的主要部位。通过阻止阿霉素在线粒体中形成氧自由基的其他策略可能会提供更强的心脏保护作用。
