Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease

Abstract

Summary A series of epidemiological, experimental and preliminary clinical trials strongly suggest that mesalazine or 5‐aminosalicyclic acid (5‐ASA) may have antineoplastic and potentially prophylactic chemopreventive properties. It is assumed that mesalazine may have similar genetic and molecular targets as nonsteroidal anti‐inflammatory drugs (NSAIDs), which is further supported by its close similarity with aspirin, differing only in its structure by the presence of an amino group at position 5 of the benzene ring. The putative chemopreventive actions include the inhibition of inflammatory cascades and/or reactions involved in cell growth and proliferation, such as cyclo‐oxygenase (COX‐1 and COX‐2), which regulate cell proliferation through the formation of prostaglandins; lipoxygenase; nuclear factor κB (NFκB), responsible for the subsequent expression of pro‐inflammatory molecules; MAP kinases and Bcl‐2, as well as the activation of apoptotic processes, such as the stimulation of intestinal sphingomyelinase. The peroxisome‐proliferator‐activated receptor δ (PPARδ), which also regulates gene transcription, is thought to play a role in both inflammatory and non‐inflammatory driven carcinogenesis. This may be another significant target. It is hypothesized that 5‐ASAs may prevent the enhancing effect of prostaglandins on PPARδ binding to DNA by its COX inhibitory properties, decreasing proliferation of colorectal mucosal cells in non‐inflammatory bowel disease patients with sporadic polyps of the large bowel.

Current and emerging therapeutic targets for IBD

“…5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .…”

“…Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .…”

Uso de mesalazina en el servicio de gastroenterología del Hospital México de enero a diciembre del 2008

“…Con respecto a esto, la literatura indica que la sulfasalazina y la mesalazina son fármacos igualmente eficaces y la diferencia radica en el perfil de efectos adversos el cual es más favorable para la mesalazina; con respecto al factor económico, la mesalazina es más costosa que la sulfasalazina, de manera que la sulfasalazina puede ser la opción preferida cuando el costo es un factor importante [8,9,10,11,12]. Sin embargo, si tomamos en cuenta la fisiopatología de las EII y las diferencias farmacocinéticas de productos como la sulfasalazina y Pentasa ® , esta última podría ser más útil en EC debido al sistema de liberación controlada de la mesalazina a lo largo del tracto gastrointestinal.…”

“…La mesalazina es tan eficaz como la sulfasalazina, la ventaja que presenta la primera es que causa menos reacciones adversas debido a que carece del componente sulfapiridina el cual es responsable de reacciones alérgicas por la sulfasalazina [8,9,10,11]. Más de un 80-90% de los pacientes que son intolerantes a la sulfasalazina van a tolerar el uso de las nuevas formulaciones de mesalazina [2].…”

Ulcerative Colitis-Associated Colorectal Cancer Prevention by 5-Aminosalicylates: Current Status and Perspectives

“…In colon cancer cell lines, ROS such as •O 2 -, •OH, hypochlorite anion, and, in particular H 2 O 2 induce frameshift mutations and inactivate the DNA mismatch repair system (Gasche et al, 2001;Chang et al, 2002). Concerning this point, several studies indicate that mesalazine is able to inhibit ROS production and/or their deleterious effects (Allgayer et al, 1992;Allgayer, 2003).…”