Galaris D, Georgellis A, Rydström J
Biochem Pharmacol. 1985 Apr 1;34(7):989-95. doi: 10.1016/0006-2952(85)90601-x.
Various aspects of the cardiotoxicity of the anthracycline derivative and antineoplastic drug daunorubicin were investigated using isolated and cultured cells from neonatal rat hearts as a model system. Treatment of the cells with concentrations of daunorubicin of the same order of magnitude as those used in chemotherapy was accompanied by marked toxic effects, e.g. a decreased or abolished contraction, and release of lactate dehydrogenase, pyruvate and oxidized glutathione to the medium. A decreased frequency of contraction appeared to be the most sensitive probe of daunorubicin toxicity, followed by release of pyruvate and oxidized glutathione/lactate dehydrogenase. Daunorubicin and/or its metabolites also bound to cellular protein and DNA. Exposure to daunorubicin was shown to be accompanied by a rapid induction of primarily DT-diaphorase and a slower induction of glutathione transferase. The latter observations are interpreted to indicate a protective role of quinone- and peroxide-metabolizing enzymes, respectively, and support the hypothesis that daunorubicin toxicity involves generation of free radical derivatives, which initiate lipid peroxidation. This conclusion is further substantiated by the demonstration that addition of daunorubicin leads to an increased oxygen consumption.
以新生大鼠心脏的分离培养细胞为模型系统，研究了蒽环类衍生物及抗肿瘤药物柔红霉素心脏毒性的各个方面。用与化疗中使用浓度相当的柔红霉素处理细胞，会伴随明显的毒性作用，例如收缩减弱或消失，以及乳酸脱氢酶、丙酮酸和氧化型谷胱甘肽释放到培养基中。收缩频率降低似乎是柔红霉素毒性最敏感的指标，其次是丙酮酸和氧化型谷胱甘肽/乳酸脱氢酶的释放。柔红霉素和/或其代谢产物也与细胞蛋白和DNA结合。结果表明，接触柔红霉素会迅速诱导主要是DT-黄递酶，并较慢地诱导谷胱甘肽转移酶。后一观察结果分别被解释为表明醌代谢酶和过氧化物代谢酶具有保护作用，并支持柔红霉素毒性涉及自由基衍生物生成从而引发脂质过氧化的假说。柔红霉素添加导致耗氧量增加的证明进一步证实了这一结论。
