Safety assessment of new anticancer compound, mitoxantrone, in beagle dogs: comparison with doxorubicin. II. Histologic and ultrastructural pathology.

Beagle dogs received either doxorubicin hydrochloride (1.75 mg/kg) or mitoxantrone (0.125 or 0.25 mg/kg) iv once every 3 weeks. These doses were equivalent to 36.05 mg/m2 of doxorubicin and 2.58 or 5.15 mg/m2 of mitoxantrone. Sequential endomyocardial biopsies were performed approximately 2 weeks after the fourth (or fifth), seventh, and ninth doses in order to monitor histopathologic and ultrastructural changes during the study. Myocardial lesions that progressed with time and dose were observed in heart samples from dogs that received doxorubicin, but not in dogs that received mitoxantrone. The myocardial lesions induced by doxorubicin were observed with cumulative doses as low as 144 mg/m2. Myocardial changes, which did not progress with time and cumulative dose, were observed in dogs that received either dose of mitoxantrone. The earliest observable evidence of doxorubicin-associated cardiotoxicity was seen morphologically in biopsy material before clinical signs of cardiotoxicity. No evidence of cardiotoxicity, either morphologic or clinical, was seen in dogs treated with the maximum tolerated dose of mitoxantrone during the course of treatment. The dog appears to be a suitable model for studying the chronic cardiotoxic effects of anthracyclines and for monitoring effects of compounds such as mitoxantrone, which show a spectrum of activity and mechanism of action similar to that of anthracycline compounds.