Chemopreventive effects of 5-ASA and UDCA in Ulcerative Colitis:
A Double-blind, Randomized Placebo-controlled Pilot Study

Patients with Ulcerative Colitis (UC), have an increased risk of developing
colorectal cancer (CRC). Endoscopic surveillance does not reduce the inherent
neoplastic potential of the colon and colectomy is associated with medical and
psychological complications. The development of safe and effective
chemopreventive treatment strategies 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, 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 the 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 process 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 dysplasia and/or CRC. Using ACF as an 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.

1) Study the chemopreventive potential of 5-ASA and UDCA in UC by evaluating
the effect of treatment with these agents on ACF number, size and rate of
dysplasia.
2) Gain mechanistic insight into the chemopreventive properties of 5-ASA and
UDCA by genome-wide array based mRNA expression analysis of UC normal colonic
mucosa before and after treatment.
3) Improve the understanding of early events in colorectal carcinogenesis by
genome-wide array based mRNA expression analysis of dysplastic ACF and UC
normal colonic mucosa.

In this pilot-study patients will be randomized to receive placebo (n=15),
5-ASA (n=15) or 5-ASA combined with UDCA (n=15) for 12 months in a
double-blinded way. At baseline and after 12 months of treatment the number,
size and endoscopic characteristics of ACF in the rectum and sigmoid will be
determined by high-magnification chromoendoscopy. Rectal biopsies of normal
mucosa will be taken at the start of the study, during sigmoidoscopy after 6
weeks of treatment and colonoscopy after 12 months of treatment. Biopsies of
ACF, if present, will be taken during colonoscopy after 12 months of treatment.
For mRNA expression profiling of dysplastic ACF abberant crypts will be
isolated from the surrounding normal mucosa and stroma using *laser capture
microdissection* (LCM) . Genome-wide mRNA expression will be analysed using
Affymetrix GeneChips. Differential expression of a subset of genes affected by
treatment and/or neoplastic transformation will be validated by real-time
PT-PCR.

There will be three groups:
1) This group will receive 5-ASA 4g (4 sachets of 1000mg) a day and UDCA in
tablets of 500mg in a dosage of 20-30 mg/kg a day
2) This group will receive 5-ASA 4g (4 sachets of 1000mg) a day and a placebo
of UDCA in tablets of 500mg in a dosage of 20-30 mg/kg a day
3) This group will receive a placebo of both drugs

The rarely occuring and reversible impairment of kidney function by 5-ASA will
be monitored regularly. For this purpose blood samples will be taken five
times; once to check whether a patient fits the inclusion criteria and four
times during the rest of the study.
Four times the patients will answer a number of questions concerning their
well-being.
Six extra hospital visits are required for this study; one for screening and
informed consent, two to undergo an endoscopic examination, one for solely
bloodsamples and two to monitor compliance to medication and two to receive
medication.
A colonoscopy and a sigmoidoscopy are generally safe examinations. The risk of
rarely occuring complications is not be increased by counting ACF or by taking
biopsies.