Mesalazine‐induced apoptosis of colorectal cancer: on the verge of a new chemopreventive era?

Abstract

Background : It is an accepted fact that non‐steroidal anti‐inflammatory drugs (NSAIDs) are potent inhibitors of colorectal carcinogenesis. However, the major disadvantages of NSAIDs are gastrointestinal and renal toxicity. We conducted a prospective pilot study on the effects of the safe salicylic acid derivative, mesalazine, on apoptosis and proliferation of tumour cells and on normal tissue in colorectal cancer patients. Methods : Patients with colorectal cancer were asked to take mesalazine enemas for 14 days. Biopsies from malignant and normal tissue were taken prior to and after this treatment. Apoptosis was scored on haematoxylin/eosin‐stained tissue sections, and cell proliferation was assessed by the proliferation marker Ki‐67. Results : Ten out of 14 patients completed the study. The apoptotic score increased significantly in the tumour samples (pre‐treatment 14.6 ± 1.3 vs. post‐treatment 19.4 ± 0.8; P < 0.03). The apoptotic index in the normal mucosa was unchanged (pre‐treatment 3.1 ± 0.4 vs. post‐treatment 2.9 ± 0.3; N.S.). The cell proliferation in malignant tissue, according to the Ki‐67 score, was hardly affected by mesalazine (pre‐treatment 522 ± 38 vs. post‐treatment 493 ± 39; N.S.). There was no effect on the Ki‐67 index of normal mucosa (pre‐treatment 24.2 ± 2.0 vs. post‐treatment 28.3 ± 2.0; N.S.). Conclusions : This pilot study conducted in patients with colorectal cancer clearly shows that mesalazine selectively induces apoptosis of tumour cells. On the basis of these findings, which need to be confirmed in larger studies, it may be speculated that 5‐ASA could be useful in the chemoprevention of colorectal cancer.

Glucagon-Like Peptide-2 and Common Therapeutics in a Murine Model of Ulcerative Colitis

“…Somewhat surprisingly, ASA treatment was also found to augment colonic crypt cell proliferation in positions 3 and 4 in normal mice, with a similar trend observed in DSS-mice. This finding stands in contrast to a previous report that ASA has no effect on human colonic proliferation (Bus et al, 1999), although it must be noted that the distribution of proliferating cells along the crypt axis was not examined in this study. Unexpectedly, no significant increase in proliferation was observed when GLP-2 was given in combination with ASA, although a trend toward an increase was noted.…”

Molecular basis of the potential of mesalazine to prevent colorectal cancer

“…Bus et al have demonstrated that 2 wk treatment with 4 g/d mesalazine enema in patient with sporadic CRC resulted in enhanced apoptosis of tumor cells, while no change was seen in the normal mucosa that surrounded the tumor lesion. Moreover, the cellular proliferation rate as assessed by means of Ki-67 expression was unchanged in both the tumor and normal tissue [20] . Studies in rodent models of CRC showed that mesalazine inhibits tumor growth and reduces the number of aberrant cryptic foci [21,22] .…”

Treatment of Diarrhea-Predominant Irritable Bowel Syndrome With Mesalazine and/or Saccharomyces Boulardii

“…Although the exact mechanism of action of mesalazine has still to be elucidated, several potential mechanisms have been suggested, including 5-aminosalicylate-induced inhibition of inflammation by interfering with the metabolism of arachidonic acid, prevention of mucosal generation of leukotrienes and prostaglandins, scavenging of free radicals and mechanisms only recently identified involving inhibition of nuclear factor-kappaB (NFB) and induction of apoptosis (6,18,31,43,47,48,55,57,59) . Additional relevant properties include changes in the production of immune globulins and diminished production of interleukin-1 and partial inhibition of platelet activating factor (PAF) expression, resulting in a decrease in leucocyte trafficking (32) .…”