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ToxSci Advance Access published online on May 24, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh172
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received February 5, 2004
Accepted May 7, 2004

Carcinogenicity

Short-term in Vitro and in Vivo Analyses for Assessing the Tumor Promoting Potentials of Cigarette Smoke Condensates

Geoffrey M. Curtin 1*, Margaret Hanausek 2, Zbigniew Walaszek 2, Arnold T. Mosberg 1, Thomas J. Slaga 2

1 Research and Development, R.J. Reynolds Tobacco Company, Winston-Salem, North Carolina, 27102
2 AMC Cancer Research Center, 1600 Pierce Street, Denver, Colorado, 80214

* To whom correspondence should be addressed. E-mail: curting{at}rjrt.com.


  Abstract

Previous studies demonstrated that repeated application of smoke condensate from tobacco-burning reference cigarettes to chemically initiated SENCAR mouse skin promotes the development of tumors in a statistically significant and dose-dependent manner, while condensate from prototype cigarettes that primarily heat tobacco promotes statistically fewer tumors. Based on the recognized correlation between sustained, potentiated epidermal hyperplasia and tumor promotion, studies were conducted to examine the utility of selected short-term analyses for discriminating between condensates exhibiting significantly different promotion activities. In vitro analyses assessing the potential for inducing cytotoxicity (ATP bioluminescence) or free radical production (cytochrome c reduction, salicylate trapping) demonstrated significant reductions when comparing condensate collected from prototype cigarettes to reference condensate. Short-term in vivo analyses conducted within the context of a mouse skin tumor promotion protocol (i.e., comparative measures of epidermal thickness, proliferative index, myeloperoxidase activity, leukocyte invasion, mutation of Ha-ras, formation of modified DNA bases) provided similar results. Reference condensate induced statistically significant and dose-dependent increases (relative to vehicle control) for nearly all indices examined, while prototype condensate possessed a significantly reduced potential for inducing changes regarded as consistent with sustained epidermal hyperplasia and/or inflammation. Collectively, these data support the contention that selected short-term analyses associated with sustained hyperplasia and/or inflammation are capable of discriminating between smoke condensates with dissimilar tumor promotion potentials. Moreover, these studies suggest that comparative measures of proliferative index and myeloperoxidase activity, both possessing favorable correlation coefficients relative to tumor formation (i.e., >=0.95 following 8 or 12 weeks promotion), may constitute reasonable endpoints for further investigation.

Key Words: tumor promotion, short-term analyses, sustained epidermal hyperplasia, inflammation .


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