Applicability of Histopathological and Biochemical Data of Anthracyclines Cardiotoxicity in Animal Studies for Regulatory Purposes

Author(s): Nikolaos Avgeros, Nektaria Kompi, Georgia Papadimitriou, Konstantinos Tsarouhas, Christina Tsitsimpikou, George EN Kass, Jean-Lou CM Dorne, Dimitrios Kouretas, Nikolaos Georgiadis

Anthracyclines are commonly used anticancer drugs with important therapeutic applications and well-known and extensively studied cardiotoxic effects in humans. In the clinical setting guidelines for assessing and treating cardiotoxicity in humans are well established. Apart from pharmaceuticals, other everyday chemicals have lately been implicated in causing cardiotoxic effects in humans, as a side effect. In the current general toxicology regulatory framework, cardiotoxicity is not a distinct endpoint and no objective criteria or reference values exist in the regulations in order to uniformly characterize cardio-toxic adverse effects observed in animal models with relevance to humans. This in depth review uses cardiotoxicity caused by anthracyclines in rat as the gold standard model and focuses on the evaluation of the most common histopathological lesions reported and the alterations observed in biomarkers of oxidative stress and inflammation of the cardiovascular function in rat studies of anthracycline induced cardiotoxicity. The present review comes as a continuation of a previous study of our group that described the echocardiographic observations of the rat anthracycline cardiotoxicity model. All these range values and histopathology findings registered could be used to differentiate normal cardiac function in animals from pathological findings indicative of cardiotoxicity and could eventually be applied to recognize possible cardiotoxic effects of everyday chemicals. The analysis of the gathered data in this review gives promising results and creates prospects for defining cardiotoxicity reference values in animal species based on the anthracycline model and eventually developing potential guidelines for assessing cardiotoxicity as a separate hazard class of everyday chemicals for regulatory purposes.