A group of chemists, biochemists and pathologists, most with a long-standing involvement in chemical carcinogenesis studies, have addressed the question of isolation and action of chemopreventive agents from the cabbage and pea. The isolation procedure will be monitored by short-term assays for anti-genotoxic and anti-promoter activities, including: (a) anti-mutagenesis in the Ames assay with benzo(a)pyrene [B(a)P] in the presence of rat liver S9 as the activating system, with 3,3 feet, 5,5 feet-tetramethylbenzidine in the presence of a ram seminal vesicle preparation (prostaglandin synthesizing system) as the activating system, and with two direct-acting substances, methylnitrosourea and methylmethane sulfonate; (b) anti-mutagenesis in a V79-hepatocyte cocultivation assay system in the presence of a nitrosamine derivative and a direct-acting mutagen; (c) protection against site-specific DNA damage produced by treatment of the hamster with N-nitrosobis(oxopropyl)amine (BOP), which affects the pancreas, and by treatment of the rat with 1,2-dimethylhydrazine (DMH), which affects the colon; (d) anti-promoter activity in a tetradecanoylphorbol acetate (TPA)-treated SENCAR mouse with epidermal ornithine decarboxylase, [3H]-deoxythymidine incorporation into epidermal DNA (autoradiography), with epidermal PGE2 levels, and hyperplasia serving as monitoring systems; (e) anti-metaplasia produced in hamster tracheal explants by B(a)P; and (f) inhibition of the nitrosation reaction in vivo and in vitro. Partially purified substances that are promising in the above tests will then be assayed for their ability to inhibit skin tumorigenesis; in an initiation-promotion protocol with DMBA as the initiator and TPA as the promoter; DMH-induced rat colon carcinogenesis; BOP-induced hamster pancreas carcinogenesis, under an initiation-promotion protocol; and B(a)P-induced hamster lung carcinogenesis. The above procedures will allow isolation of cancer chemopreventive agents and their pharmacokinetics will be determined. In addition, we will assess the activity in the above systems of two flavonoids, robinetin and apigenin, of benzylisothiocyanate and of indole-3-carbinol. The goal of this phase of the proposed research is to better define the chemopreventive action of benzylisothiocyanate and indole-3-carbinol, to determine whether the two flavonoids have such property, and to determine the pharmacokinetics of these compounds.
|Holtz, G; Bresnick, E (1988) Ascorbic acid inhibits the squamous metaplasia that results from treatment of tracheal explants with asbestos or benzo[a]pyrene-coated asbestos. Cancer Lett 42:23-8|
|Birt, D F; Pelling, J C; Pour, P M et al. (1987) Enhanced pancreatic and skin tumorigenesis in cabbage-fed hamsters and mice. Carcinogenesis 8:913-7|
|Birt, D F; Walker, B; Tibbels, M G et al. (1986) Anti-mutagenesis and anti-promotion by apigenin, robinetin and indole-3-carbinol. Carcinogenesis 7:959-63|