Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents.
Foci of aberrant and/or hexosaminidase-negative crypts in rat colon are putative precancerous lesions that have been proposed as biomarkers for short-term bioassays for chemical carcinogens and chemopreventive agents. The ability of a substance to reduce the yield of azoxymethane (AOM)-induced foci in the colon of male Fischer 344 rats, was evaluated as a screening assay for chemopreventive agents. Twenty-eight test agents were administered continuously in the diet from the start of the experiments until the animals were killed 35 days later. AOM was s.c. administered either as 15 mg/kg body wt on days 7 and 14 or as 30 mg/kg body wt on day 7 of the experiment. Foci of aberrant crypts were evaluated in whole mounts of methylene blue-stained colons. AOM induced twice as many foci when administered between 8.40 and 11.00 a.m. than between 2.45 and 5.55 p.m. Calcium salts of carbonate, chloride and glucarate decreased the yield of AOM-induced foci while the acidic salts of lactate and phosphate did not inhibit the formation of foci. Dimethyl-fumarate, fumaric acid, genistein, piroxicam, simethicone, sodium suramin and sulindac reduced the yield of AOM-induced foci of aberrant crypts, with genistein being the most potent. Only piroxicam of this group has previously been shown to inhibit colon cancer, while the rest have yet to be evaluated. Ibuprofen did not inhibit the formation of foci, although it has been reported to inhibit AOM-induced colon cancer in rats. Piroxicam and sulindac appeared to reduce preferentially hexosaminidase-negative foci of aberrant crypts, compared with those of apparently normal morphology. The AOM-induced foci of aberrant crypts assay appears suitable for screening chemicals for chemopreventive action.
Pereira
M A
MA
Environmental Health Research and Testing Inc., Lexington, KY 40503.
Barnes
L H
LH
Rassman
V L
VL
Kelloff
G V
GV
Steele
V E
VE
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001397:Azoxymethane; D001835:Body Weight / Q000187:drug effects; D002940:Circadian Rhythm; D003106:Colon / Q000187:drug effects / Q000201:enzymology; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D004354:Drug Screening Assays, Antitumor; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D016588:Anticarcinogenic Agents; D001619:beta-N-Acetylhexosaminidases; D001397:Azoxymethane