Preclinical toxicity of the new antineoplastic agent, ametantrone acetate, in mice and dogs.

Ametantrone acetate (anthracenedione diacetate, NSC 287513) is an experimental antineoplastic agent with activity against a comprehensive panel of solid transplantable tumors in mice and dogs were carried out to establish tolerable levels. In mice, LD10, LD50 and LD90 values were respectively, 26, 35 and 47 mg kg-1 28 days following single intravenous injection and 22, 67 and 206 mg kg-1 14 days after single intraperitoneal injection. Hemorrhage and necrosis of the small intestine occurred in intercurrent deaths. A 5-day, consecutive intraperitoneal dosing study yielded 28 day, LD10, LD50 and LD90 values of 18, 21 and 26 mg kg-1, respectively, in mice. Bone marrow hypoplasia, lymphoid depletion and focal cardiac changes were observed in animals which died during the 28-day postdose observation period. In dogs, single intravenous injections repeated twice at intervals of 3-8 weeks resulted in leukopenia and thrombocytopenia at a dose of 2.71 mg kg-1 and decreased myeloid: erythroid ratios at a dose of 0.68 mg kg-1. Five consecutive daily intravenous injections in dogs of 0.7 mg kg-1 induced significant clinical and laboratory signs of toxicity but 0.35 mg kg-1 day-1 was tolerated. In dogs, bone marrow, lymphoid tissue and gastro-intestinal tract in both sexes and gonads in the males were target organs for toxicity. Clinical signs and clinical laboratory abnormalities abated in surviving mice and dogs. The spectrum of tissue changes induced by ametantrone was qualitatively similar to that elicited with other intercalating agents.