Reduction of aberrant crypt formation in the colon of CF1 mice by potential chemopreventive agents.
Carcinogen-induced aberrant crypts (AC) of the colon are a precancerous state that leads to malignancy. The inhibition of AC formation by chemopreventive agents was evaluated in this study. Colon AC were induced by 1,2-dimethylhydrazine (DMH) in 3 weeks in CF1 mice. The cecum of the large intestine of CF1 mice did not produce more than one AC focus per animal. The effect of DMH and that of the inhibitors in this part of the large bowel were essentially similar to the vehicle control and inhibitor-only controls. The response of DMH treatment in the colorectal portion of the large bowel was found to be different from that of the cecum. The DMH treated mice had 13-17 foci per animal in three different experiments. The average number of AC per focus was greater than one in all three experiments performed. None of the inhibitor-only control animals nor the cottonseed oil vehicle control animals developed AC focus in the colorectal or the cecal part of the large bowel. The known inhibitor of colon carcinogenesis 3-butyl-4-hydroxyanisole reduced DMH-induced average AC formation by 10 and 46% at 1 and 4 mg per dose, respectively. The inhibitors 2-n-butylthiophene and phenylpropylisothiocyanate reduced DMH-induced average AC formation greater than 34 and greater than 40% respectively. The postulated inhibitor 2-n-octylthiophene, which is an eight-carbon homolog of 2-n-butylthiophene, similarly reduced DMH-induced AC formation. The known colon carcinogenesis inhibitor dehydroepiandrosterone, in contrast, has no effect. The inactivity of dehydroepiandrosterone to inhibit colon AC formation was attributed to its mechanism of inhibitory action, which differs from that of the phenol, isothiocyanate and thiophenes. The short duration that is required to produce quantifiable results suggests that the reduction of carcinogen-induced AC formation may be developed into a useful prescreening assay for potential chemopreventive agents against colon cancer.
Lam
L K
LK
Gray Freshwater Biological Institute, University of Minnesota, Navarre 55392.
Zhang
J
J
D019813:1,2-Dimethylhydrazine; D000818:Animals; D002083:Butylated Hydroxyanisole / Q000627:therapeutic use; D002432:Cecum / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004127:Dimethylhydrazines; D005260:Female; D008751:Methylene Blue; D051379:Mice; D008815:Mice, Inbred Strains; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013876:Thiophenes / Q000627:therapeutic use
D004127:Dimethylhydrazines; D013876:Thiophenes; C072020:2-n-butylthiophene; D002083:Butylated Hydroxyanisole; C051362:3-tert-butyl-4-hydroxyanisole; C072021:2-n-octylthiophene; D019813:1,2-Dimethylhydrazine; D008751:Methylene Blue