Comparison of doxorubicin- and MEN 10755-induced long-term progressive cardiotoxicity in the rat

The delayed functional cardiotoxic effects of repeated treatment with the n ew disaccharide anthracycline MEN 10755 and doxorubicin (1.5 mg/kg, i.v., o nce a week for 5 consecutive weeks) were investigated in the rat. Changes w ere assessed (2 days and 4 and 13 weeks after the last treatment) in ECG mo rphology, hemodynamics, in vivo left ventricular contractile responses to b eta-adrenergic stimulation, and histopathology of both atria and ventricles . Doxorubicin induced significant and progressive prolongation of the Q alp ha T interval starting 2 days after suspension of treatment. At 4 and 13 we eks after the last treatment, the ECG showed a further progressive and sign ificant impairment. MEN 10755 induced alterations similar in nature but of lesser severity compared with doxorubicin. In addition, MEN 10755-induced p rolongation of the Q alpha T interval was nor progressive, being similar at 4 and 13 weeks after the last treatment. Although the hemodynamics were on ly slightly affected by both anthracyclines, a nearly complete ablation of isoprenaline-induced enhancement of ventricular function was observed 4 and 13 weeks after the last treatment with doxorubicin, whereas only mild, if any, reduction was detected in rats receiving MEN 10755. Histopathologic in vestigations indicated that both anthracyclines produced qualitatively simi lar alterations in ventricular myocytes. However, only with doxorubicin did these changes show a progression with a further significant worsening at 1 3 weeks as compared with 4 weeks after the last treatment. In addition, atr ial lesions were evident in doxorubicin-treated rats, but not in rats recei ving MEN 10755. In conclusion, an equimyelotoxic regimen of MEN 10755 produ ced, as compared with doxorubicin, lesser ECG alterations, smaller impairme nt of the ventricular response to adrenergic stimulation, and less severe m yocyte lesions. Unlike doxorubicin, the histologic and functional cardiotox ic effects induced by MEN 10755 were not progressive. Further investigation s are warranted to define the pharmacodynamic and/or pharmacokinetic mechan ism(s) underlying the different cardiotoxic profile exhibited by the two an thracyclines.