Skip Navigation



ToxSci Advance Access published online on May 28, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg141
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
74/2/271    most recent
kfg141v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Thompson, K. L.
Right arrow Articles by Sistare, F. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Thompson, K. L.
Right arrow Articles by Sistare, F. D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received December 20, 2002; accepted April 9, 2003
© 2003 Society of Toxicology

Carcinogenicity

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

Karol L. Thompson 1*, Barry A. Rosenzweig 1, James L. Weaver 1, Jun Zhang 1, Karl K. Lin 2, Frank D. Sistare 1

1 Division of Applied Pharmacology Research, Office of Testing & Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation & Research, FDA, Laurel, MD 20708
2 Division of Biometrics II, Office of Biostatistics, Office of Pharmacoepidemiology & Statistical Science, Center for Drug Evaluation & Research, FDA, Laurel, MD 20708

* To whom correspondence should be addressed. E-mail: Thompsonk{at}cder.fda.gov.


  Abstract

Understanding the strengths and limitations of alternative models, such as the Tg.AC assay, for evaluation of the potential carcinogenicity of pharmaceuticals requires assessment of assay specificity through studies that specifically target biologically active compounds that are known to not be carcinogens in rodents. To identify drugs that might provoke a false positive response in the Tg.AC assay, we screened pharmaceuticals for in vitro induction of the gadd153 promoter and the {zeta}-globin promoter. We have previously found a high correlation between induction of the gadd153 promoter in HepG2 cells and activity in the Tg.AC assay. The three drugs selected through screening 100 noncarcinogenic pharmaceuticals were amiloride, dipyridamole, and pyrimethamine. A 26-week skin paint study was conducted in hemizygous Tg.AC mice with the 3 drugs at two doses selected by a four-week dose range finding study. Evidence of systemic toxicity was observed in animals dosed chronically with pyrimethamine or amiloride, but no skin papillomas were observed in mice treated with amiloride, dipyridamole, or pyrimethamine for 26 weeks. All male mice and 80% of female mice treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) in acetone developed a maximal tumor burden. However, mice treated with TPA in a vehicle containing 2.4% DMSO had greatly reduced incidences of papillomas. In summary, the correct negative response was shown in the Tg.AC assay for 3 noncarcinogenic pharmaceuticals, which adds further favorable evidence of appropriate specificity of this model system. However, vehicle composition must be carefully selected because the outcome of this assay can be confounded by certain commonly used solvents.

Key Words: Tg.AC, gadd153, TPA, DMSO, Solvent .


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.