Duxorubicin-induced cardiotoxicity.

ABSTRACT

The survival rate of cancer patients has greatly increased over the last 20 years. However, to achieve this result, a considerable price has been paid in terms of the side-effects associated with the intensive anticancer treatment. Cardiotoxicity of anticancer drugs is a serious problem. It is defined, by the National Cancer Institute, as the “toxicity that affects the heart.” This definition not only includes a direct effect of the drug on the heart, but also an indirect effect due to enhancement of hemodynamic flow alterations or due to thrombotic events. Cardiotoxicity can develop in a subacute, acute, or chronic manner. The risk for such effects depends upon cumulative dose, rate of drug administration, mediastinal radiation, advanced age, younger age, female gender, pre-existing heart disease and hypertension. Anthracyclines, such as doxorubicin (DOX), cause serious cardiac side-effects. Acute tachyarrhythmias and acute heart failure (HF) may occur after high doses, but these reactions are now rare due to changed dosage schemes (e.g. slower infusion) with the aim to prevent this. However, the sub-acute or chronic cardiac effects of anthracyclines remain a clinical problem. Clinically, anthracycline induced cardiotoxicity manifests itself as left ventricular failure, which develops insidiously over months to years after completion of the anthracycline based chemotherapy and may result in congestive HF. The mechanism of anthracyclin induced cardiotoxicity is not totally unraveled. It is likely that the decline in myocardial function is related to apoptosis of cardiac myocytes that occurs apparently at random in the myocardium. Anthracyclin induced formation of reactive oxygen species (ROS) in the presence of intracellular iron, impaired homeostasis of intracellular iron and calcium (that may facilitate the apoptosis induced by the ROS) have been put forward as mechanisms. Cardiac protection can be achieved by limitation of the cumulative dose. Further, addition of the antioxidant and iron chelator dexrazoxane to anthracycline therapy has shown to be effective in lowering the incidence of anthracycline induced cardiotoxicity.