AIMS The clinical application of doxorubicin is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of doxorubicin (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies. METHODS AND RESULTS We treated domestic pigs with either doxorubicin, epirubicin, or liposomal doxorubicin and compared the cardiac, laboratory and hemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers NT-proBNP and Troponin I and an impact on body weight. High morbidity of epirubicin-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in doxorubicin-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes, linked to DNA damage repair and cell survival, were downregulated by doxorubicin, but upregulated by liposomal doxorubicin in both the left and right ventricle. The expression of cardioprotective translocator protein TSPO was inhibited by doxorubicin, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups. CONCLUSIONS All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of doxorubicin induced interferon-stimulated genes in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.

中文翻译：

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脂质体阿霉素通过诱导干扰素相关的DNA损伤抗性来减轻心脏毒性。

目的阿霉素的心脏毒性作用严重影响了阿霉素的临床应用，从而限制了治疗指数和累积剂量。阿霉素脂质体包囊（Myocet®）通过减少心肌药物的积聚提供一定的抗心脏毒性的保护作用。我们的目标是在翻译性大型动物模型中评估对具有不同心脏毒性谱的蒽环类药物的转录组反应，以确定潜在的缓解策略。方法和结果我们用阿霉素，表柔比星或阿霉素脂质体处理了家猪，并与盐水处理的动物比较了其心脏，实验室和血液动力学的影响。在所有组中都遇到心脏毒性，这反映在血浆标志物NT-proBNP和肌钙蛋白I的增加以及对体重的影响上。表柔比星治疗的动物高发病率阻碍了进一步评估。与用脂质体制剂治疗的动物相比，用late后期增强和经胸超声心动图检查的心脏磁共振成像显示，阿霉素处理动物的左，右心室收缩功能降低更强，心肌纤维化更强。通过RNA测序分析左心室和右心室的基因表达谱，并通过qPCR验证。与DNA损伤修复和细胞存活有关的干扰素刺激基因被阿霉素下调，但脂质体阿霉素在左心室和右心室中均上调。阿霉素可抑制心脏保护转运蛋白TSPO的表达，但脂质体制剂则不会。在所有治疗组中均发现具有胶原蛋白激活的心脏纤维化。结论所有蒽环类衍生物均导致胶原蛋白合成和加工的转录激活。阿霉素诱导的干扰素刺激基因的脂质体包装与较低的心脏毒性有关，这在抗癌治疗中具有重要的临床意义。我们的研究确定了合理制定缓解蒽环类药物所致心肌病策略的潜在机制。