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首页> 外文期刊>Journal of applied toxicology >The minipig as a new model for the evaluation of doxorubicin-induced chronic toxicity
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The minipig as a new model for the evaluation of doxorubicin-induced chronic toxicity

机译：小型猪作为评估阿霉素诱导的慢性毒性的新模型

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Doxorubicin can cause life-threatening toxic effects in several organs, with cardiotoxicity being the major concern. Although a large number of animal models have been utilized to study doxorubicin toxicity, several restrictions limit their use. Since the Gottingen minipig is an accepted species for non-clinical safety assessment and translation to man, we aimed at exploring its use as a non-rodent animal model for safety assessment and regulatory toxicity studies using doxorubicin. Three groups of three males and three females adult Gottingen minipigs received 1.5mgkg(-1), 3/2.3mgkg(-1) or vehicle at intervals of 3weeks for 7cycles. Doxorubicin treatment resulted in a dose-related decrease in the erythrocytes, hemoglobin and hematocrit count, accompanied by leukopenia and thrombocytopenia. Bone marrow smears revealed dose-related hypocellularity. Urea and creatinine levels were elevated in treated animals, associated with proteinuria and hematuria. Histopathological evaluation detected nephropathy and atrophy of hematopoietic tissues/organs, mucosa of the intestinal tract and male genital tract. Cardiac lesions including chronic inflammation, endocardial hyperplasia, hemorrhage and myxomatous changes were evident in hematoxylin and eosin stains, and evaluation of semi-thin sections showed the presence of dose-related vacuolation in the atrial and ventricular cardiomyocytes. Cardiac troponin levels were increased in the high-dose group, but there was no direct correlation to the severity of the histopathological lesions. This study confirms that the Gottingen minipig has a comparable toxicity profile to humans and considering its anatomical, physiological, genetic and biochemical resemblance to humans, it should be considered as the non-rodent species of choice for studies on doxorubicin toxicity. Copyright (c) 2015 John Wiley & Sons, Ltd.
机译：阿霉素可在多个器官中引起威胁生命的毒性作用，心脏毒性是主要关注的问题。尽管已经使用了大量的动物模型来研究阿霉素的毒性，但是一些限制限制了它们的使用。由于哥廷根小型猪是公认的用于非临床安全性评估和转化为人类的物种，因此我们旨在探索其作为非啮齿类动物模型的安全性评估和使用阿霉素进行监管毒性研究的用途。三组三只雄性和三只雌性成年的哥廷根小型猪接受1.5mgkg（-1），3 / 2.3mgkg（-1）或媒介剂，间隔3周，共7个周期。阿霉素治疗导致红细胞，血红蛋白和血细胞比容计数与剂量有关，并伴有白细胞减少症和血小板减少症。骨髓涂片显示剂量相关的细胞减少。在治疗的动物中，尿素和肌酐水平升高，与蛋白尿和血尿有关。组织病理学评估发现肾病和造血组织/器官，肠道粘膜和男性生殖道萎缩。在苏木精和曙红染色中，明显发现了包括慢性炎症，心内膜增生，出血和粘液瘤样改变在内的心脏病变，对半薄切片的评估显示在心房和心室心肌细胞中存在剂量相关的空泡化。大剂量组心脏肌钙蛋白水平升高，但与组织病理学病变的严重程度没有直接关系。这项研究证实，哥廷根小型猪具有与人类相当的毒性，并且考虑到其在解剖学，生理，遗传和生化方面与人类相似，因此应将其视为阿霉素毒性研究的非啮齿类动物。版权所有（c）2015 John Wiley＆Sons，Ltd.

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