Chemopreventive effects of mesalazine in patients at high risk of recurrent (nonfamilial) colorectal adenomas

Patients with sporadic colorectal adenomatous polyps removed by polypectomy
have a high rate of polyp recurrence and carry an increased risk for the
development of colorectal carcinoma (CRC). Chemoprevention may lower the rate
of adenoma recurrence after polypectomy, thereby reducing the risk of CRC
development. Unlike NSAIDs mesalazine is an attractive candidate for
chemoprevention, since even during long-term use it has only limited systemic
adverse effects and no gastrointestinal toxicity. In a prospective trial a
trend towards reduced adenoma recurrence has been observed in high risk
patients with a history of at least 3 sporadic colorectal adenomas treated with
mesalazine. Identification of biologically relevant antineoplastic properties
of mesalazine in patients with sporadic adenomatous polyps will support further
investigation of mesalazine as chemopreventive agent against colorectal
neoplasia in the sporadic setting. Growth inhibition of colonic epithelial
cells through induction of apoptosis and inhibition of proliferation is widely
recognized as a potential mechanism for chemoprevention of colorectal cancer.
In vivo data suggest that mesalazine exerts pro-apoptotic and
anti-proliferative effects on normal colorectal epithelial cells. Furthermore,
there is in vitro evidence in CRC cells that mesalazine inhibits Wnt/β-catenin
signalling, an early and common inappropriately activated pathway in colorectal
carcinogenesis and molecular target for chemoprevention.

1) Identify chemopreventive properties of mesalazine in patients at high risk
of recurrent (nonfamilial) colorectal adenomas by evaluating the effect of
treatment on apoptosis and proliferation in histologically normal sigmoid and
rectal mucosa relative to the placebo group.
2) Identify chemopreventive properties of mesalazine in patients at high risk
of recurrent (nonfamilial) colorectal adenomas by evaluating the effect of
treatment on expression of beta-catenin signalling pathway components in
histologically normal sigmoid and rectal mucosa relative to the placebo group.

double-blind, randomized placebo-controlled study

Treatment with 3.0 g mesalazine or placebo once daily for 6 months. At baseline
and after 6 months of treatment, a sigmoidoscopy will be performed and biopsies
of normal appearing sigmoid and rectal mucosa will be collected.

Very rarely renal and liver disorders occur as a result from using mesalazine.
In general these resolve after the use of mesalazine is discontinued. Four
times during the study period blood samples will be drawn to check renal and
liver function.
Five additional hospital visits are required for this study; one for screening
and informed consent, twice to undergo a sigmoidoscopy and twice for adverse
effects evaluation and compliance monitoring. During four of these visits a
questionnaire concerning use of concomitant medication and nutritional
supplements has to be completed.
A sigmoidoscopy is in general a safe examination with rarely complications
occuring. Risk increase due to biopsy taking is negligible.