source: Translational research

year: 2007

authors: Berkhout M, Roelofs H M, Friederich P, van Schaik A, Gosens M J, Marian B, Pool-Zobel B L, van Krieken J H, Peters W H, Nagengast F M

Familial adenomatous polyposis (FAP), which is caused by mutations in the Adenomatous Polyposis Coli(APC) gene, is characterized by numerous colorectal adenomas that inevitably will progress to adenocarcinoma when left untreated by colectomy. The duodenum is the main site for (pre-)malignant extracolonic manifestations in these patients. The prevalences of the mainly peri-ampullary adenomas and duodenal carcinomas varies from 50% to 90% and 2% to 5% respectively. Both incidence and severity of the duodenal adenomatosis increases with age, and because of the colectomy, the FAP population is getting on in years, which implies that the problems with respect to duodenal adenomas and carcinomas will further increase.

The clustering of adenomas around the Ampulla of Vater suggests that bile plays a role in their formation and/or progression. However, ursodeoxycholic acid (UDC), a tertiary bile acid hardly present in human bile, may act as a chemopreventive drug. Wali et al found an inhibiting effect of UDC on the induction of cyclooxygenase-2 (COX-2), a key enzyme in regulation of cell proliferation, in an animal model of colonic carcinogenesis. Furthermore, a combination of UDC and sulindac was proven effective in the prevention of intestinal adenomas in a mouse model of FAP. Until now, the treatment of duodenal adenomas in patients with FAP has been restricted to surgical intervention with concomitant high morbidity and mortality. New therapies, such as chemoprevention of duodenal adenomas/carcinomas in patients with FAP would be highly preferable. Therefore, we performed a pilot intervention study with UDC in 5 patients with FAP to find out whether UDC is tolerated. In addition, we studied the effects on bile acid composition, cytotoxicity and genotoxicity of duodenal bile, sampled before and after the intervention period. We also studied whether the duodenal COX-2 expression levels were influenced by the UDC intervention.