This Article Free Full Text (Free PDF) Free References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Holden, H. E. Articles by Blanchard, K. T. Search for Related Content PubMed PubMed Citation Articles by Holden, H. E. Articles by Blanchard, K. T. Social Bookmarking                         What's this?

Oxymetholone: II. Evaluation in the Tg.AC Transgenic Mouse Model for Detection of Carcinogens

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

Toxicologic Pathology, Vol. 27, No. 5, 507-512 (1999)
DOI: 10.1177/019262339902700502


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				F. D. Sistare, K. L. Thompson, R. Honchel, and J. DeGeorge Evaluation of the Tg.AC Transgenic Mouse Assay for Testing the Human Carcinogenic Potential of Pharmaceuticals--Practical Pointers, Mechanistic Clues, and New Questions International Journal of Toxicology, January 1, 2002; 21(1): 65 - 79. [Abstract] [PDF]

				W. C. Eastin, J. H. Mennear, R. W. Tennant, R. E. Stoll, D. G. Branstetter, J. R. Bucher, B. Mccullough, R. L. Binder, J. W. Spalding, and J. F. Mahler Tg.AC Genetically Altered Mouse: Assay Working Group Overview of Available Data Toxicol Pathol, January 1, 2001; 29(1_suppl): 60 - 80. [Abstract] [PDF]

				H. E. Holden, D. Studwell, and J. B. Majeska Oxymetholone: I. Evaluation in a Comprehensive Battery of Genetic Toxicology and In Vitro Transformation Assays Toxicol Pathol, September 1, 1999; 27(5): 501 - 506. [Abstract] [PDF]

				R. E. Stoll, H. E. Holden, C. H. Barthel, and K. T. Blanchard Oxymetholone: III. Evaluation in the p53+/- Transgenic Mouse Model Toxicol Pathol, September 1, 1999; 27(5): 513 - 518. [Abstract] [PDF]