PROMOTIONAL ACTIVITIES OF THE NONGENOTOXIC CARCINOGEN BEMITRADINE (SC-33643)

Bemitradine (SC-33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2-year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg-1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5-15% in the female and 10-12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg-1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms. The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC-36741; desethylbemitradine) were tested and found to be non-genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK +/- (bemitradine only) assays. Finally, in an altered hepatic foci (Y-glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promoter, though not as potent as phenobarbital. We concluded that bemitradine (which has been dropped from development) is a non-genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.