Experimental systemic toxicology of 4'-epidoxorubicin, a new, less cardiotoxic anthracycline antitumor agent.

The acute and chronic iv toxicity of 4'-epidoxorubicin, a new antitumor anthracycline antibiotic, was compared with doxorubicin. The LD50 of 4'-epidoxorubicin was 16.07 mg/kg in mice, 14.27 mg/kg in rats, and about 2 mg/kg in dogs; the LD50 of doxorubicin was 11.98 mg/kg in mice, 10.51 mg/kg in rats, and about 2.5 mg/kg in dogs. Rats and dogs were also dosed iv for 91 days (3 injections/week) with 4'-epidoxorubicin or doxorubicin at doses of 0.128, 0.32, and 0.8 mg/kg to rats and 0.064, 0.16, and 0.4 mg/kg to dogs. A comprehensive toxicological evaluation of the animals was carried out before, throughout, and at the end of the study. High-dose 4'-epidoxorubicin induced toxic clinical signs in dogs, and in both species caused loss of body weight, antiproliferative effects on blood-forming organs and testes, and degenerative lesions in kidneys and heart. The cardiac damage was moderate in rats and very mild in dogs; only three male rats died at this dose. The medium dose induced less pronounced changes and no heart lesions and the low dose was practically nontoxic. Doxorubicin showed similar antiproliferative activity, but more evident toxic effects, especially on the heart; many rats given the high dose died and some at the medium dose showed initial cardiac lesions. Thus 4'-epidoxorubicin appeared less toxic than doxorubicin; in particular cardiac damage was much less evident in animals chronically injected with the new drug.