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ToxSci Advance Access originally published online on October 5, 2005
Toxicological Sciences 2006 89(1):66-74; doi:10.1093/toxsci/kfi343
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Short-Term Biomarkers of Cigarette Smoke Condensate Tumor Promoting Potential in Mouse Skin

Geoffrey M. Curtin*,1, Margaret Hanausek{dagger}, Zbigniew Walaszek{dagger}, Robert Zoltaszek{dagger}, James E. Swauger*, Arnold T. Mosberg* and Thomas J. Slaga{dagger}

* Research and Development, R. J. Reynolds Tobacco Company, Winston-Salem, North Carolina 27102; and {dagger} The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229

Received June 4, 2005; accepted September 23, 2005

Previous studies demonstrated that cigarette smoke condensates (CSCs) possessing significantly different tumorigenic potentials according to a standardized 30-week mouse skin tumor-promotion protocol could likewise be discriminated utilizing short-term indices of sustained hyperplasia and/or inflammation (G. M. Curtin et al., 2004, Toxicol. Sci. 81, 14–25). The current study employed a truncated initiation-promotion protocol to further evaluate CSC-induced hyperplasia, examining issues related to time course of induction, existence of a threshold and suitable dynamic range for detectable responses, and reversibility. Condensate application (9–36 mg "tar"/200-µl application, thrice-weekly for 3–15 weeks) induced treatment-related increases for epidermal thickness, proliferative index as assessed by 5-bromo-2'-deoxyuridine (BrdU) labeling, and ornithine decarboxylase (ODC) expression. Interestingly, observed increases for interfollicular BrdU labeling and ODC expression were partially reversed but still elevated upon cessation of promotion, while increases within the perifollicular epidermis remained elevated at a level similar to that observed during CSC application. In particular, assessments based on perifollicular ODC expression would appear to provide a greater opportunity for test article discrimination based on a rapid time to induction, a low threshold and expanded dynamic range of responses, and the potential to account for irreversible changes. These findings are particularly intriguing based on reports suggesting that ODC expression may be necessary for tumor promotion and that mouse skin tumors originate primarily within the perifollicular epidermis.

Key Words: tumor promotion; hyperplasia; ornithine decarboxylase; perifollicular epidermis.


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