Evaluation of chemopreventive agents in different mechanistic classes using a rat tracheal epithelial cell culture transformation assay.
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.
Arnold
J T
JT
Cellular and Molecular Toxicology Program, ManTech Environmental Technology, Research Triangle Park, North Carolina 27709.
Wilkinson
B P
BP
Sharma
S
S
Steele
V E
VE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000145:classification* / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004848:Epithelium; D005978:Glutathione / Q000378:metabolism; D006633:Histamine Antagonists / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D012176:Retinoids / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D001095:Arachidonic Acids; D006633:Histamine Antagonists; D065108:Ornithine Decarboxylase Inhibitors; D012176:Retinoids; D001564:Benzo(a)pyrene; D011493:Protein Kinase C; D005978:Glutathione