CRC chemoprevention in UC.

Patients with Ulcerative Colitis (UC), have an increased risk of developing colorectal cancer (CRC). Endoscopic surveillance does not reduce inherent neoplastic potential of the colon and colectomy is associated with medical and psychological complications. The developement of a safe and effective chemopreventive treatment strategy for reducing the overall risk of neoplasia would thus be of substantial benefit to UC patients. Epidemiological case-control studies have indicated that the regular use of 5-aminosalicylic acid (5-ASA) may reduce the risk of developing CRC in UC. Furthermore, 5-ASA and ursodeoxycholic acid (UDCA) has been demonstrated to suppress colitis-associated colon carcinogenesis in mice. Moreover, two retrospective studies have shown that patients with Primary Sclerosing Cholangitis (PSC) and UC had a significantly lower risk of developing dysplasia and CRC than non-treated patients. A recent study in patients with IBD and PSC also suggested that de combined use of 5-ASA and UDCA further decreases the risk of colorectal dysplasia development. Aberrant crypt foci (ACF) are considered to be the earliest identifiable preneoplastic lesions in the multistep proces of colorectal carcinogenesis. Recently, it has been reported that the number of ACF in the rectum increases from patients with UC and no dysplasia, to those with dysplasia and further to UC patients with CRC. Using ACF as a biological end-point rather than the number of colonic tumours has the advantage of a shorter study duration with generation of quantifiable results. Insight into the mechanism of chemopreventive properties of 5-ASA and UDCA has come from studies using CRC cells or animal models of inflammation. We speculate however that identifying the molecular targets in human colonocytes will provide more powerful insight into the mechanisms by which these agents impact neoplastic transformation.

5-ASA and UDCA have a chemopreventive potential in UC.

1. Baseline: Informed consent, Clinical Activity Index, Bloodsamples, Colonoscopy & staining, Rectal/Sigmoid biopsies NM;

2. 4 Weeks: Compliance, Adverse effects questionnaire, Bloodsamples;

3. 12 Weeks: Compliance, Adverse effects questionnaire, Bloodsamples;

4. 20 Weeks: Compliance, Adverse effects questionnaire, Bloodsamples;

5. 32 Weeks: Compliance, Adverse effects questionnaire, Bloodsamples;

6. 52 Weeks: Clinical Activity Index, Compliance, Adverse effects questionnaire, Bloodsamples, Colonoscopy & staining, Rectal/sigmoid biopsies NM, Rectal/sigmoid biopsies ACF.

There are three groups:

1. This group will receive 5-ASA: 4 g a day (4 sachets of 1000mg granu-stix) and UDCA 20-25 mg/kg/day (500mg tablets);

2. This group will receive 5-ASA: 4 g a day (4 sachets of 1000mg granu-stix) and a placebo of UDCA 20-25 mg/kg/day(500mg tablets);

3. This group will receive a placebo of 5-ASA: 4 g a day (4 sachets of 1000mg granu-stix) and a placebo of UDCA 20-25 mg/kg/day (500mg tablets).



Medication will be used during 1 year.