Reis-Mendes Ana Filipa, Sousa Emília, de Lourdes Bastos Maria, Costa Vera Marisa
REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Curr Drug Metab. 2015;17(1):75-90. doi: 10.2174/1389200216666151103114926.
Cardioncology is a major topic of the day, since cardiotoxicity of chemotherapy agents can limit its real use and it can also become a clinical problem years after the end of anticancer therapy. These cardiac problems largely increase the mortality and morbidity of cancer-treated patients. Actually, as the number of cancer survivors is increasing each decade, late cardiotoxicity related to anticancer therapy is expected to grow exponentially in the fore coming years. The mechanisms of cardiotoxicity of anticancer drugs are still largely unknown. The metabolism of some drugs can lead to more active anticancer metabolites but those metabolites can likewise contribute to the observed cardiotoxicity. The alcohols and aglycone metabolites of anthracyclines are known to be cardiotoxic, while regarding 5-fluorouracil, fluoroacetate is considered one of the major metabolites responsible for its cardiotoxicity. Regarding mitoxantrone, the toxicity of the majority of the metabolites has not been assessed so far and concerning cyclophosphamide metabolites, both hydroxycyclophosphamide and acrolein are shown to be more cardiotoxic than the parent drug. Still, the contribution of drug metabolism to the cardiotoxicity of chemotherapy agents is largely unknown and poorly discussed. This review presents a new link between several cardiotoxic anticancer drugs and their drug metabolites, as they can play an important role in the widely reported heart damage inflicted by chemotherapy. Anthracyclines, cyclophosphamide, mitoxantrone, and 5- fluorouracil will be mainly focused, given the vast literature and clinical use. The current knowledge shows the possible involvement of drug metabolism in bioactivation mechanisms that can contribute to their cardiotoxicity.
心脏肿瘤学是当今的一个重要话题，因为化疗药物的心脏毒性会限制其实际应用，并且在抗癌治疗结束数年之后还可能成为一个临床问题。这些心脏问题极大地增加了癌症患者的死亡率和发病率。实际上，随着每十年癌症幸存者数量的增加，预计未来几年与抗癌治疗相关的迟发性心脏毒性将呈指数级增长。抗癌药物的心脏毒性机制在很大程度上仍然未知。某些药物的代谢可产生更具活性的抗癌代谢物，但这些代谢物同样可能导致所观察到的心脏毒性。已知蒽环类药物的醇类和苷元代谢物具有心脏毒性，而就5-氟尿嘧啶而言，氟乙酸盐被认为是导致其心脏毒性的主要代谢物之一。至于米托蒽醌，到目前为止大多数代谢物的毒性尚未得到评估，而就环磷酰胺代谢物而言，羟基环磷酰胺和丙烯醛均显示出比母体药物更强的心脏毒性。然而，药物代谢对化疗药物心脏毒性的作用在很大程度上仍然未知且很少被讨论。本综述提出了几种具有心脏毒性的抗癌药物与其药物代谢物之间的新联系，因为它们在化疗所致的广泛报道的心脏损伤中可能起重要作用。鉴于大量的文献和临床应用，将主要聚焦于蒽环类药物、环磷酰胺、米托蒽醌和5-氟尿嘧啶。目前的知识表明药物代谢可能参与了可导致其心脏毒性的生物活化机制。
