The Role of the Metabolism of Anticancer Drugs in Their Induced-Cardiotoxicity

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.