Cardiotoxicity and cytotoxicity of the anthracycline analog 4′-deoxy-4′-iodo-doxorubicin

Abstract

The cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4′-deoxy-4′-iodo-DXR were evaluated and compared to DXR. A single dose of DXR 10 mg/kg i.v. in anesthetized rats induced a significant widening of SαT segment of the electrocardiogram, an increase in both mean arterial blood pressure and heart rate and a fall in systematic arterial dP dt max , while 4′-deoxy-4′-iodo-DXR 4 mg/kg i.v. induced a significant widening of SαT segment and an increase in mean arterial blood pressure. A chronic cardiomyopathy was induced over a 6-week period by three injections of DXR 3 mg/kg per week i.v. and was characterized by a progressive enlargement of SαT segment, a flattening of T wave, the occurrence of arrhythmias and histological alterations of myocardium. The contractile responses to adrenaline of isolated hearts from DXR-treated animals were significantly reduced compared to controls. 4′-Deoxy-4′-iodo-DXR (1.2 mg/kg per week three times) induced minor ECG alterations and sporadic episodes of arrhythmias. The contractile responses of isolated hearts were not significantly different from those of controls and microscopic examination of hearts revealed only minor changes. Cytotoxicity in vitro was evaluated by the colony formation assay; based on IC 50, 4′-deoxy-4′-iodo-DXR was up to six times more cytotoxic than DXR on four human cancer cell lines. These results suggest that 4′-deoxy-4′-iod-DXR is significantly less cardiotoxic and more cytotoxic and more cytotoxic than DXR.