Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat.
We assessed the effects of 41 potential chemopreventive agents in the F344 rat using the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon as the measure of efficacy. ACF were induced by the carcinogen azoxymethane in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last azoxymethane injection, animals were evaluated for the number of aberrant crypts detected in methylene blue-stained whole mounts of rat colon. The 41 agents were derived from a priority listing that was based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. The list of agents included representative examples of phytochemicals, vitamins, minerals, inhibitors of proliferation, inducers of Phase 1 and Phase 2 metabolism systems, nonsteroidal anti-inflammatory agents, and differentiation agents. Eighteen agents were positive in the assay, significantly reducing the incidence of ACF at least in one of two doses tested. As a chemical class, the nonsteroidal anti-inflammatory drugs, which included ibuprofen, ketoprofen, piroxicam, and indomethacin, were most active; other less potent agents were arginine, butylated hydroxyanisole, curcumin, diallyl sulfide, difluoromethylornithine, 18 beta-glycyrrhetinic acid, indole-3-carbinol, oltipraz, purpurin, rutin, and the sodium salts of butyrate, selenite, and thiosulfate. Twenty-three agents did not inhibit ACF; included among these were several agents that promoted the development of ACF at one or both doses tested: benzyl isothiocyanate,calcium glucarate, catechin, dihydroepiandosterone, fluocinolone acetonide,folic acid, levamisole, 2-mercaptoethanesulfonic acid, nordihydroguiaretic acid, potassium glucarate, propyl gallate, beta-sitosterol, sodium cromolyn, sodium molybdate, and sulfasalazine. The aberrant crypt assay demonstrates reasonable specificity and sensitivity in predicting which agents are likely to prevent colon cancer.
Wargovich
M J
MJ
Department of Gastrointestinal Medical Onclolgy and Digestive Diseases, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
Chen
C D
CD
Jimenez
A
A
Steele
V E
VE
Velasco
M
M
Stephens
L C
LC
Price
R
R
Gray
K
K
Kelloff
G J
GJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001397:Azoxymethane / Q000009:adverse effects; D014408:Biomarkers, Tumor; D002273:Carcinogens / Q000009:adverse effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018890:Chemoprevention; D003106:Colon / Q000187:drug effects / Q000473:pathology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D004396:Coloring Agents; D005069:Evaluation Studies as Topic; D005544:Forecasting; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008751:Methylene Blue; D008903:Minerals / Q000627:therapeutic use; D011237:Predictive Value of Tests; D051381:Rats; D011916:Rats, Inbred F344; D012680:Sensitivity and Specificity; D014815:Vitamins / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D002273:Carcinogens; D004396:Coloring Agents; D008903:Minerals; D014815:Vitamins; D001397:Azoxymethane; D008751:Methylene Blue