Safety assessment of a new anticancer compound, mitoxantrone, in beagle dogs: comparison with doxorubicin. I. Clinical observations

Abstract

Twenty-four adult beagle dogs were divided into four groups of three males and three females and received iv infusions of doxorubicin (36.05 mg/m2), mitoxantrone (2.58 or 5.15 mg/m2), or the vehicle (0.9% normal saline). All animals were given a single dose once every 3 weeks. The duration of the study was 30 weeks. Animals were observed for toxicologic and cardiotoxic signs. The methods used to evaluate the cardiotoxic potential of both mitoxantrone and doxorubicin were sequential endomyocardial biopsies, ECGs, blood pressure, and serum levels of the cardiospecific isoenzyme CPK-MB (MB band of CPK). Animals given mitoxantrone had signs of gastrointestinal toxicity and fluctuating decreases in wbc counts. Animals given doxorubicin had signs of gastrointestinal toxicity and cardiotoxicity, as well as alopecia, fluctuating decreases in wbc counts, and diffuse erythema. All three male animals given doxorubicin died during the study from apparent congestive heart failure. All dogs treated with doxorubicin had positive CPK isoenzyme elevation, ECG changes, or progressive cardiomyopathy prior to administration of the last dose. None of these signs was observed in dogs treated with mitoxantrone. One male dog given mitoxantrone died during the course of the study.