Chemoprevention of azoxymethane-induced colonic carcinogenesis by supplemental dietary ursodeoxycholic acid.
The present studies were conducted at the Universities of Chicago and Arizona to examine and compare the effects of supplemental dietary ursodeoxycholic acid to cholic acid, a known tumor promoter, and to piroxicam, a known chemopreventive agent, in the azoxymethane (AOM) model of experimental colonic carcinogenesis. Male Fischer 344 rats were utilized in these experiments. All animals were fed a basal diet (AIN-76) supplemented with 0.2% or 0.4% cholic acid, 0.2% or 0.4% ursodeoxycholic acid, 0.2% ursodeoxycholic acid plus 0.2% cholic acid, or 75 ppm piroxicam. Rats were given s.c. injections once a week for 2 weeks with AOM (15 mg/kg body wt/week) or vehicle (saline) after being fed their respective diets for 2 weeks. The rats in each group were then maintained on their respective diets for approximately 28 weeks; after sacrifice, their colons were removed and examined macroscopically and microscopically for the presence of tumors. The results of these studies demonstrated that none of the control rats fed the various diets injected with AOM-vehicle developed tumors. In groups receiving AOM, the addition of cholic acid (0.4%) caused a significant increase in the incidence of tumors. In contrast, the addition of 0.2% ursodeoxycholic acid did not promote AOM-induced colonic tumors, and when it was added to a promoting dose of cholic acid (0.2%), 0.2% ursodeoxycholic acid prevented enhancement of tumor promotion. At higher doses (0.4%), supplemental dietary ursodeoxycholic acid significantly reduced the incidence of colon tumors and cancers. Moreover, the tumor suppressive effects of 0.4% ursodeoxycholic acid exceeded that of dietary piroxicam. Our results further emphasize the important role of bile salts in modulating colonic tumor development. These studies also demonstrate for the first time that supplemental dietary ursodeoxycholic acid is a chemopreventive agent in the AOM model of experimental colonic carcinogenesis.
Earnest
D L
DL
Department of Medicine, University of Arizona, Tucson 85721.
Holubec
H
H
Wali
R K
RK
Jolley
C S
CS
Bissonette
M
M
Bhattacharyya
A K
AK
Roy
H
H
Khare
S
S
Brasitus
T A
TA
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D001397:Azoxymethane / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D004032:Diet; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage*
D016588:Anticarcinogenic Agents; D014580:Ursodeoxycholic Acid; D001397:Azoxymethane