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 Weaver, J. L. Articles by Sistare, F. D. Search for Related Content PubMed PubMed Citation Articles by Weaver, J. L. Articles by Sistare, F. D. Social Bookmarking                         What's this?

An Evaluation of the Hemizygous Transgenic Tg.AC Mouse for Carcinogenicity Testing of Pharmaceuticals. I. Evidence for a Confounding Nonresponder Phenotype

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Joseph F. Contrera

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Barry A. Rosenzweig

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Karol L. Thompson

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Patrick J. Faustino

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

John M. Strong

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Christopher D. Ellison

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Lawrence W. Anderson

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Hullahalli R. Prasanna

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Patricia E. Long-Bradley

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Karl K. Lin

Office of Epidemiology and Biostatistics, Office of Review Management, Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, Maryland 20708

Jun Zhang

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

Frank D. Sistare

Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Laurel, Maryland 20708

We have completed 2 26-wk studies to evaluate the hemizygous transgenic Tg.AC mouse, which has been proposed as an alternative short term model for testing carcinogenicity. We attempted to evaluate the response to the known rodent carcinogens cyclophosphamide, phenolphthalein, and tamoxifen and to the noncarcinogen chlorpheniramine following topical application. In the first study, a weak response (2/17 animals) was observed to the positive control 12-O-tetradecanoylphorbol 13-acetate (TPA in ethanol, 1.25 µg), and no response was observed to cyclophosphamide, phenolphthalein, or chlorpheniramine, despite evidence for skin penetration. The second study compared 1.25 µg and 6.25 µg of TPA in ethanol and acetone solutions. Tamoxifen was also evaluated in both solvents and orally. No significant response was observed to tamoxifen by skin paint or oral routes. Over 60% of the high dose TPA-treated animals showed no (0 or 1) papilloma response, and 30% of the animals each developed more than 32 papillomas. The heterogenous response to high dose TPA may be related to variability in the responsiveness of hemizygous animals. In light of these findings, further Tg.AC studies should employ homozygous animals, and the underlying cause for heterogeneity in the tumorigenic response of Tg.AC mice should be identified and eliminated.

Key Words: Papillomagenesis • cyclophosphamide • chlorpheniramine • phenolphthalein • skin • tamoxifen • 12-o-tetradecanoylphorbol 13-acetate • zeta-globin

Toxicologic Pathology, Vol. 26, No. 4, 532-540 (1998)
DOI: 10.1177/019262339802600409


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

This article has been cited by other articles:

				R. D. Verschoyle, R. Edwards, B. Nolan, and P. Greaves Articular Chondromatosis and Chrondroid Metaplasia in Transgenic TAg Mice Toxicol Pathol, January 1, 2004; 32(1): 22 - 25. [Abstract] [PDF]

				S. R. Payne and C. J. Kemp p27 Kip1 (Cdkn1b)-Deficient Mice Are Susceptible to Chemical Carcinogenesis and May Be a Useful Model for Carcinogen Screening Toxicol Pathol, June 1, 2003; 31(4): 355 - 363. [Abstract] [PDF]

				B. Bolon and E. Galbreath Use of Genetically Engineered Mice in Drug Discovery and Development: Wielding Occam's Razor to Prune the Product Portfolio International Journal of Toxicology, January 1, 2002; 21(1): 55 - 64. [Abstract] [PDF]

				R. W. Tennant, S. Stasiewicz, W. C. Eastin, J. H. Mennear, and J. W. Spalding The Tg.AC (v-Ha-ras) Transgenic Mouse: Nature of the Model Toxicol Pathol, January 1, 2001; 29(1_suppl): 51 - 59. [Abstract] [PDF]

				C. T. Siegel, K. Schreiber, S. C. Meredith, G. B. Beck-Engeser, D. W. Lancki, C. A. Lazarski, Y.-X. Fu, D. A. Rowley, and H. Schreiber Enhanced Growth of Primary Tumors in Cancer-Prone Mice after Immunization against the Mutant Region of an Inherited Oncoprotein J. Exp. Med., June 5, 2000; 191(11): 1945 - 1956. [Abstract] [Full Text] [PDF]

				D. Gulezian, D. Jacobson-Kram, C. B. Mccullough, H. Olson, L. Recio, D. Robinson, R. Storer, R. Tennant, J. M. Ward, and D. A. Neumann Review Article: Use of Transgenic Animals for Carcinogenicity Testing: Considerations and Implications for Risk Assessment Toxicol Pathol, May 1, 2000; 28(3): 482 - 499. [Abstract] [PDF]

				J. W. Spalding, J. E. French, S. Stasiewicz, M. Furedi-Machacek, F. Conner, R. R. Tice, and R. W. Tennant Responses of Transgenic Mouse Lines p53+/- and Tg•AC to Agents Tested in Conventional Carcinogenicity Bioassays Toxicol. Sci., February 1, 2000; 53(2): 213 - 223. [Abstract] [Full Text] [PDF]

				K. L. Thompson, B. A. Rosenzweig, and F. D. Sistare An Evaluation of the Hemizygous Transgenic Tg.AC Mouse for Carcinogenicity Testing of Pharmaceuticals. II. A Genotypic Marker that Predicts Tumorigenic Responsiveness Toxicol Pathol, July 1, 1998; 26(4): 548 - 555. [Abstract] [PDF]

				R. R. Maronpot The Potential of Genetically Altered Mice as Animal Models for Carcinogen Identification Toxicol Pathol, July 1, 1998; 26(4): 579 - 581. [PDF]