Chronic Cardiotoxicity Studies in Rabbits with 7-con-O-Methylnogarol, a New Anthracycline Antitumor Agent

Abstract 7- con-O -Methylnogarol (7-OMEN), a new analog of the anthracycline antibiotic, nogalamycin, has chemotherapeutic activity in several experimental mouse tumor systems. As part of the preclinical development of 7-OMEN, the cardiotoxic potential was evaluated in chronically dosed rabbits. Groups of 4 rabbits were dosed twice weekly i.v. with 11 or 33 mg/sq m/week for 12 weeks, 110 sq m/mg/week for 12 or 24 weeks, or 154 mg/sq m/week for 24 weeks to give cumulative doses of 132, 396, 1319, 2640, or 3700 mg/sq m, respectively. Histological studies showed minimal evidence of cardiotoxicity in rabbits which received 1319 mg/sq m or lower doses of 7-OMEN. However, the characteristic anthracycline-induced cardiac lesions (vacuolization, myocytolysis, and fibrosis) were present in mild to marked amounts in 8 of 8 rabbits which received cumulative doses of 2640 or 3700 mg/sq m. One rabbit in the 3700 mg/sq m group exhibited excess pericardial fluid; no other gross symptoms of cardiac toxicity were present. None of the 7-OMEN-treated rabbits died from cardiotoxicity. Four Adriamycin-treated control rabbits died of drug-induced cardiomyopathy and congestive heart failure at 222 to 277 mg/sq m. Thus, 7-OMEN was less than one-fifteenth as potent as was Adriamycin in inducing cardiotoxicity in rabbits. 7-OMEN given at 220 mg/sq m/week for 3 to 4 weeks caused lethal bone marrow depression in 4 of 4 rabbits. At lower doses, 7-OMEN caused a mild to moderate, dose-related, regenerative, macrocytic anemia which was most severe approximately halfway through the 24-week study and then improved despite continuous twice-weekly dosing.