Sun X, Zhou Z, Kang Y J
Departments of Medicine, and Pharmacology and Toxicology, University of Louisville, School of Medicine, Louisville, KY 40202, USA.
Cancer Res. 2001 Apr 15;61(8):3382-7.
Previous studies have shown that cardiac-specific metallothionein (MT)-overexpressing transgenic mice are highly resistant to acute cardiotoxicity induced by doxorubicin (DOX), a most effective anticancer agent. However, cumulative dose-dependent chronic cardiotoxicity attributable to long-term administration of DOX is a significant clinical problem. Because MT is a potent antioxidant and oxidative stress is critically involved in DOX-induced heart injury, the present study was undertaken to test the hypothesis that MT also provides protection against DOX chronic cardiotoxicity. Transgenic mice containing high levels of cardiac MT and nontransgenic controls were treated with a cumulative dose of 40 mg/kg of DOX in 10 equal i.v. injections over a period of 7 weeks. Three weeks after the last injection, the mice were killed for an analysis of cardiotoxicity. As compared with nontransgenic controls, DOX-induced cardiac hypertrophy was significantly inhibited in the transgenic mice. Light microscopic examination revealed that DOX-induced myocardial morphological changes were markedly suppressed or almost eliminated in the transgenic mice. Under electron microscopy, extensive sarcoplasmic vacuolization and severe disruption of mitochondrial fine structure were observed in nontransgenic cardiomyocytes, but almost no sarcoplasmic vacuolization was observed, and the mitochondrial structural changes were almost completely prevented in the transgenic cardiomyocytes. The results thus indicate that MT elevation is a highly effective approach to prevent chronic cardiomyopathy attributable to DOX. This study also suggests that oxidative stress is critically involved in the DOX-induced chronic cardiotoxicity.
先前的研究表明，心脏特异性金属硫蛋白（MT）过表达的转基因小鼠对阿霉素（DOX，一种最有效的抗癌药物）诱导的急性心脏毒性具有高度抗性。然而，长期给予DOX导致的累积剂量依赖性慢性心脏毒性是一个重大的临床问题。由于MT是一种有效的抗氧化剂，且氧化应激在DOX诱导的心脏损伤中起关键作用，因此本研究旨在验证MT也能预防DOX慢性心脏毒性这一假说。将含有高水平心脏MT的转基因小鼠和非转基因对照小鼠，在7周内通过10次等量静脉注射给予累积剂量为40 mg/kg的DOX。最后一次注射后3周，处死小鼠以分析心脏毒性。与非转基因对照相比，转基因小鼠中DOX诱导的心脏肥大受到显著抑制。光学显微镜检查显示，转基因小鼠中DOX诱导的心肌形态学变化明显受到抑制或几乎消除。在电子显微镜下，非转基因心肌细胞中观察到广泛的肌浆空泡化和线粒体精细结构的严重破坏，但转基因心肌细胞中几乎未观察到肌浆空泡化，并且线粒体结构变化几乎完全得到预防。因此，结果表明MT升高是预防DOX所致慢性心肌病的一种非常有效的方法。本研究还表明，氧化应激在DOX诱导的慢性心脏毒性中起关键作用。
