Oxymetholone: II. Evaluation in the Tg.AC transgenic mouse model for detection of carcinogens

Several rodent models are under examination as possible alternatives to the classical 2-yr carcinogenicity bioassay. The Tg.AC transgenic mouse has be en proposed as a shorter term model offering the possibility of detecting n ongenotoxic and genotoxic carcinogenic agents. Retrospective studies of che micals with established carcinogenic potential have revealed a close correl ation between classical bioassay results and the production of skin tumors in the Tg.AC mouse model. Oxymetholone is a synthetic testosterone derivati ve that is a suspected carcinogen but has shown no evidence of genotoxic ac tivity in a comprehensive battery of genetic toxicity assays. It currently is being tested by the National Toxicology Program (NTP) in a 2-yr rat carc inogenicity bioassay. Because of its nongenotoxicity and the ongoing chroni c bioassay, oxymetholone was considered an ideal candidate for a prospectiv e evaluation of the predictive validity of the Tg.AC dermal carcinogenicity model. Consequently, a 6-mo dermal study with oxymetholone in the Tg.AC mo use model was initiated and completed prior to disclosure of the NTP rat bi oassay results. In this study, male and female hemizygous Tg.AC mice, 7-8 w k old, were housed individually in suspended plastic cages. An area of dors al skin was shaved to accommodate dermal applications of 200-mu 1 doses of vehicle control (acetone), drug (1.2, 6.0, or 12 mg oxymetholone in dimethy lsulfoxide:acetone, 20:80), or positive control (1.25 mg 12-o-tetradecanoyl -phorbol-13-acetate [TPA]) solutions. Mice received oxymetholone or acetone daily or TPA twice weekly for 20 wk followed by a 6-wk recovery period. Th e acetone control groups exhibited low spontaneous incidences of papillomas , whereas dermal application of oxymetholone produced dose-related increase s in the numbers of papilloma-bearing mice and the numbers of papillomas pe r animal. Females showed a somewhat greater response to the androgen than d id the males. TPA caused an unequivocal increase in papillomas, with males exhibiting a greater response than females. The results of this study indic ate that this nongenotoxic androgenic compound possesses proliferative prop erties. The results predict that chronic systemic administration of oxymeth olone will most likely be associated with increased incidences of neoplasms .