Document Detail


Ursodeoxycholate/Sulindac combination treatment effectively prevents intestinal adenomas in a mouse model of polyposis.
MedLine Citation:
PMID:  15362039     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Preclinical studies in animal models, human epidemiological data, and clinical trials in patients with adenomatous polyposis have consistently indicated that sulindac and other nonsteroidal antiinflammatory drugs or cyclooxygenase inhibitors have the greatest potential efficacy among current candidates for colon tumor chemopreventive agents. However, at highly effective doses they all have some risk of toxicity, and their therapeutic profile might be improved by use at lower, more tolerable doses, in combination with a second agent acting via other mechanisms. METHODS: Sulindac was tested in combination with ursodeoxycholic acid (ursodiol), a naturally occurring 7-B-epimer of the bile component chenodeoxycholic acid, for prevention of adenomas in the Min mouse model of adenomatous polyposis. RESULTS: Ursodeoxycholic acid caused a dose-dependent decrease in the number of intestinal tumors. Unlike sulindac and other nonsteroidal anti-inflammatory drugs, which are quite beneficial in the distal intestine but are somewhat less effective in the proximal small intestine (especially the clinically important periampullary duodenum), ursodeoxycholate had equal efficacy throughout the entire intestine, both proximal and distal. Combined treatment with low-dose sulindac was less toxic, with normal weight gain and fewer gastrointestinal ulcerations than high-dose sulindac. Combined treatment with sulindac and ursodeoxycholate was more effective than either agent alone for the prevention of tumors throughout the entire intestine. CONCLUSIONS: These experiments provide the first evidence that ursodeoxycholic acid is effective for preventing adenomas in an animal model. Cyclooxygenase inhibition, when combined with this naturally occurring bile component, may become a promising approach for colon cancer prevention.
Authors:
Russell F Jacoby; Carolyn E Cole; E T Hawk; R A Lubet
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Gastroenterology     Volume:  127     ISSN:  0016-5085     ISO Abbreviation:  Gastroenterology     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-09-13     Completed Date:  2004-10-19     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  838-44     Citation Subset:  AIM; IM    
Affiliation:
University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, USA. rfjacoby@wisc.edu
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MeSH Terms
Descriptor/Qualifier:
Adenomatous Polyps / prevention & control*
Animals
Anticarcinogenic Agents / administration & dosage
Chemoprevention / methods
Cholagogues and Choleretics / administration & dosage*
Cyclooxygenase Inhibitors / administration & dosage*
Dose-Response Relationship, Drug
Drug Synergism
Intestinal Polyposis / prevention & control*
Mice
Mice, Inbred C57BL
Models, Animal
Sulindac / administration & dosage*
Ursodeoxycholic Acid / administration & dosage*
Grant Support
ID/Acronym/Agency:
N01 CN 65122/CN/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Anticarcinogenic Agents; 0/Cholagogues and Choleretics; 0/Cyclooxygenase Inhibitors; 128-13-2/Ursodeoxycholic Acid; 38194-50-2/Sulindac

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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