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Oxymetholone: II. Evaluation in the Tg.AC Transgenic Mouse Model for Detection of Carcinogens
Henry E. Holden
Department of Toxicology and Safety Assessment, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877
Raymond E. Stoll
Department of Toxicology and Safety Assessment, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877
Kerry T. Blanchard
Department of Toxicology and Safety Assessment, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877
Several rodent models are under examination as possible alternatives to the classical 2-yr carcinogenicity bioassay. The Tg.AC transgenic mouse has been proposed as a shorter term model offering the possibility of detecting nongenotoxic and genotoxic carcinogenic agents. Retrospective studies of chemicals with established carcinogenic potential have revealed a close correlation between classical bioassay results and the production of skin tumors in the Tg.AC mouse model. Oxymetholone is a synthetic testosterone derivative that is a suspected carcinogen but has shown no evidence of genotoxic activity in a comprehensive battery of genetic toxicity assays. It currently is being tested by the National Toxicology Program (NTP) in a 2-yr rat carcinogenicity bioassay. Because of its nongenotoxicity and the ongoing chronic bioassay, oxymetholone was considered an ideal candidate for a prospective evaluation of the predictive validity of the Tg.AC dermal carcinogenicity model. Consequently, a 6-mo dermal study with oxymetholone in the Tg.AC mouse model was initiated and completed prior to disclosure of the NTP rat bioassay results. In this study, male and female hemizygous Tg.AC mice, 7-8 wk old, were housed individually in suspended plastic cages. An area of dorsal skin was shaved to accommodate dermal applications of 200-µl doses of vehicle control (acetone), drug (1.2, 6.0, or 12 mg oxymetholone in dimethylsulfoxide: acetone, 20:80), or positive control (1.25 µg 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. The acetone control groups exhibited low spontaneous incidences of papillomas, whereas dermal application of oxymetholone produced dose-related increases in the numbers of papilloma-bearing mice and the numbers of papillomas per animal. Females showed a somewhat greater response to the androgen than did the males. TPA caused an unequivocal increase in papillomas, with males exhibiting a greater response than females. The results of this study indicate that this nongenotoxic androgenic compound possesses proliferative properties. The results predict that chronic systemic administration of oxymetholone will most likely be associated with increased incidences of neoplasms.
Key Words: Oxymetholone • Tg.AC • transgenic mouse • carcinogenicity • papillomas
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Toxicologic Pathology, Vol. 27, No. 5,
507-512 (1999)
DOI: 10.1177/019262339902700502
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