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Evaluation of Chemopreventive Agents in Different Mechanistic Classes Using a Rat Tracheal Epithelial Cell Culture Transformation Assay¹

Cellular and Molecular Toxicology Program, ManTech Environmental Technology, Research Triangle Park, North Carolina 27709 [J. T. A., B. P. W., S. S.], and Chemoprevention Branch, Division of Cancer Prevention and Control, National Cancer Institute, NIH, Bethesda, Maryland 20892 [V. E. S.]

The rat tracheal epithelial (RTE) cell focus inhibition assay was used to identify potential chemopreventive agents. Ninety-nine agents were evaluated for their ability to inhibit benzo[a]pyrene-induced transformation of RTE cells. Freshly isolated RTE cells were exposed to benzo[a]pyrene alone or in combination with a chemopreventive agent. After 30 days in culture, transformed foci were scored and inhibition was quantitated. In these studies, foci formation was inhibited mainly by agents which modulate the initiation of carcinogenesis by altering drug-metabolizing enzymes, inhibiting the binding of benzo[a]pyrene to DNA, enhancing detoxification of activated carcinogens, or by inducing epithelial cell differentiation. Such agents include antioxidants, free radical scavengers, glutathione S-transferase enhancers, vitamins, retinoids, and sulfhydryl compounds. Agents which inhibit ornithine decarboxylase and arachidonic acid metabolism were not as effective. The RTE assay provides important data for agent selection prior to whole animal-screening assays in the development of chemoprevention drugs.

¹ Supported by the National Cancer Institute Contracts N01-CN-55503-05, N01-CN-95172-02, and N01-CN-95172-06.

² Present address: Department of Pathology, CB #7525, University of North Carolina, Chapel Hill, NC 27599-7525.

³ To whom requests for reprints should be addressed, at ManTech Environmental Technology, P.O. Box 12313, Research Triangle Park, NC 27709.

Received 8/ 8/94. Accepted 12/ 1/94.

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