C022 Experimental approaches of oxidative stress and cardiotoxicity associated with anthracyclines administration

The chronic cardiotoxicity of anthracyclines anticancer drugs is one of the main factors which limits their prolonged use. Clinically, this cardiotoxicity results in a cardiomyopathy with irreversible congestive heart failure with high mortality. The molecular mechanisms, which could explain this cardiac toxicity, are complex but seem distinct from the anticancer mechanism. Several hypotheses were advanced, but it appears that the production of reactive oxygen and nitrogen species (RONS) constitutes the common denominator.In a first study, we evaluated the acute effect of epirubicin administration on the evolution of cardiac functional parameters and production of RONS. Isolated perfused rat hearts were subjected to 70minutes of epirubicin (10.3μm) infusion. RONS were detected in the coronary effluents by electron spin resonance spectroscopy with a spin probe, 1-hydroxy-3-carboxy-pyrrolidine (CP-H, 0.1mm). Epirubicin induced a reduction in coronary flow and in left ventricular developed pressure (p<0.001). RONS was 2.5 times greater in the epirubicin group than in the control group (p<0.05).In a second study, we observed that, in a mouse model of anthracyclines-induced cardiotoxicity (20mg/kg i.p. of doxorubicin or epirubicin), the cardiac functional alterations evaluated by echocardiography were associated with an increase in ascorbyl radical / ascorbate ratio (p