|
Sign In to gain access to subscriptions and/or personal tools.
|
An Evaluation of the Hemizygous Transgenic Tg.AC Mouse for Carcinogenicity Testing of Pharmaceuticals. II. A Genotypic Marker that Predicts Tumorigenic Responsiveness
Karol L. Thompson
Division of Applied Pharmacology Research, Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, Maryland 20708
Barry A. Rosenzweig
Division of Applied Pharmacology Research, Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, Maryland 20708
Frank D. Sistare
Division of Applied Pharmacology Research, Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, Maryland 20708
The Tg.AC transgenic mouse skin paint assay is one of the short-term carcinogenesis models that has been proposed as a replacement for 1 species in the conventional 2-yr bioassay required for safety testing of pharmaceuticals. In our initial efforts to evaluate the sensitivity and specificity of this model for human pharmaceuticals, 61% of the hemizygous Tg.AC mice in the positive control groups were refractory to treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA). Tg.AC mice are reported to carry  10 copies of a transgcne consisting of a  -globin promoter fused to the v-Ha-ras structural gene with a terminal simian virus 40 (SV40) polyaden-ylation signal. Southern blot hybridization of genomic DNA from 66 tail biopsies using a -globin probe revealed that all of the hemizygous Tg.AC mice screened contained approximately 40 copies of the transgene and that mice unresponsive to TPA had lost a 2-kb BamHI fragment containing -gIobin promoter sequence. By systematic screening of Tg.AC breeder mice for this diagnostic marker of phenotypic responsiveness, it should be possible to selectively enrich the Tg.AC mouse colony to consist exclusively of responders and to guard against further genetic instability.
Key Words: Gene amplification • genetic instability • inverted repeat • palindrome • 12-O-tetradecanoylphorbol 13-acetate • Southern blot hybridization • zeta-globin
Toxicologic Pathology, Vol. 26, No. 4,
548-555 (1998)
DOI: 10.1177/019262339802600411
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
S. Chanda, G. Erexson, D. Frost, S. Babbar, J.-A. Burlew, and K. Bley
26-Week Dermal Oncogenicity Study Evaluating Pure trans-Capsaicin in Tg.AC Hemizygous Mice (FBV/N)
International Journal of Toxicology,
March 1, 2007;
26(2):
123 - 133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Thompson and F. D. Sistare
Selection of Drugs to Test the Specificity of the Tg.AC Assay by Screening for Induction of the gadd153 Promoter in Vitro
Toxicol. Sci.,
August 1, 2003;
74(2):
260 - 270.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Thompson, B. A. Rosenzweig, J. L. Weaver, J. Zhang, K. K. Lin, and F. D. Sistare
Evaluation of the Tg.AC Assay: Specificity Testing with Three Noncarcinogenic Pharmaceuticals that Induce Selected Stress Gene Promoters in Vitro and the Inhibitory Effects of Solvent Components
Toxicol. Sci.,
August 1, 2003;
74(2):
271 - 278.
[Abstract]
[Full Text]
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
R. E. Stoll, S. M. Furst, J. H. Stoltz, P. D. Lilly, and J. H. Mennear
Dermal Carcinogenicity in Transgenic Mice: Effect of Vehicle on Responsiveness of Hemizygous Tg.AC Mice to Phorbol 12-Myristate 13-Acetate (TPA)
Toxicol Pathol,
August 1, 2001;
29(5):
535 - 540.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
K. L. Thompson, B. A. Rosenzweig, Y. Tsong, and F. D. Sistare
Evaluation of in Vitro Reporter Gene Induction Assays for Use in a Rapid Prescreen for Compound Selection to Test Specificity in the Tg.AC Mouse Short-Term Carcinogenicity Assay
Toxicol. Sci.,
September 1, 2000;
57(1):
43 - 53.
[Abstract]
[Full Text]
[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]
|
|
|
|
|
|
|
J. L. Weaver, J. F. Contrera, B. A. Rosenzweig, K. L. Thompson, P. J. Faustino, J. M. Strong, C. D. Ellison, L. W. Anderson, H. R. Prasanna, P. E. Long-Bradley, et al.
An Evaluation of the Hemizygous Transgenic Tg.AC Mouse for Carcinogenicity Testing of Pharmaceuticals. I. Evidence for a Confounding Nonresponder Phenotype
Toxicol Pathol,
July 1, 1998;
26(4):
532 - 540.
[Abstract]
[PDF]
|
|
|
|
|
|
|
K. T. Blanchard, D. J. Ball, H. E. Holden, S. M. Furst, J. H. Stoltz, and R. E. Stoll
Dermal Carcinogenicity in Transgenic Mice: Relative Responsiveness of Male and Female Hemizygous and Homozygous Tg.AC Mice to 12-O-Tetradecanoylphorbol 13-Acetate (TPA) and Benzene
Toxicol Pathol,
July 1, 1998;
26(4):
541 - 547.
[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]
|
|
|
|
|
