Chemoprevention of N-methylnitrosourea-induced colon carcinogenesis by ursodeoxycholic acid-5-aminosalicylic acid conjugate in F344 rats.
Bile acids enhance colon carcinogenesis in animal models, whereas ursodeoxycholic acid (UDCA) suppresses it. Nonsteroid anti-inflammatory drugs prevent colon cancer development in animals and humans. The aim of the present study was to explore the inhibitory effect of UDCA conjugate with 5-aminosalicylic acid (5-ASA), UDCA-5-ASA conjugate (UDCA-5-ASA), against colon carcinogenesis in rats. One-hundred-and-twenty-nine 7-week-old F344 rats received an intrarectal instillation of 2 mg of N-methylnitrosourea 3 times a week for 3 weeks, and were fed a 0% (control), 0.11% or 0.02% UDCA-5-ASA-, 0.08% UDCA- or 0.03% 5-ASA-supplemented diet for the next 27 weeks. The test diets contained an equimolar amount of a test agent, 2.0 mmol/kg diet, except for the 0.02% UDCA-5-ASA diet. The tumor incidence and the mean number of tumors/rat at week 30 were significantly lower and smaller in the UDCA-5-ASA diet groups, 48% and 0.7 in both, and marginally lower in the UDCA and 5-ASA diet groups, 56% and 0.9, and 64% and 0.8, compared to the control group, 83% and 1.3. All the tumors were polypoid in shape, and most of them were differentiated adenocarcinomas restricted to the mucosa or submucosa. An analysis by HPLC for bile acids and 5-ASA in the feces and serum collected at week 30 showed that one-half of ingested UDCA-5-ASA was cleaved into UDCA and 5-ASA in the colon. Thus, the two moieties may have independently affected the promotion stage of carcinogenesis.
Narisawa
Tomio
T
Akita University College of Allied Medical Sciences, Akita 010-8543, Japan.
Fukaura
Yoko
Y
Takeba
Naomi
N
Nakai
Keiko
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000032:analysis; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D005260:Female; D019804:Mesalamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008770:Methylnitrosourea; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D014580:Ursodeoxycholic Acid / Q000493:pharmacokinetics / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D001647:Bile Acids and Salts; D019804:Mesalamine; D008770:Methylnitrosourea; D014580:Ursodeoxycholic Acid