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

Abstract

Ulcerative Colitis from Genetics to Complications 150 hypothesis have emerged, resulting from fundamental research in molecular biology and pharmacology. This increased understanding of the putative pathway(s) by which 5-ASA may interfere with CAC development appears also as the starting point for optimising 5-ASA derivatives or identifying new compounds acting more specifically and/or being more efficient in preventing neoplastic transformation of the colonic epithelium in UC patients. These different points will be addressed more precisely in the three next parts. Frequency of colorectal cancer risk in ulcerative colitis and risk factors

Spontaneous and transgenic rodent models of inflammatory bowel disease

“…There are several different systems that have been used to characterize histological lesions observed in IBD, but classical histological interpretation of mixed inflammatory cellular infiltrates can be very subjective due to their occurrence in response to non-IBD related disease etiologies, and also because a uniform set of prognostic biomarkers has not yet been fully developed in human or veterinary medicine for CD or UC diagnosis [ 3 11 ]. Most small animal IBD patients are initially treated with diet restrictions, use of metronidazole to change the intestinal microbiota by eliminating anaerobic bacterial species; increased fiber content and anti-inflammatory products [ 12 20 ]. Human UC and CD patients are treated using first line therapies, including oral mesalamine, sulfasalazine for colitis only, Budesonide oral corticosteroid and oral proton pump inhibitors such as omeprazole.…”

“…Increasingly, newly introduced tumor necrosis factor antibody and other inhibitors are improving the success of human IBD therapy [ 21 ], and have been introduced in animal models to examine underlying pathogenic mechanisms [ 22 23 ]. If initial treatment measures are not effective second line immunosuppressive therapy such as high dose prednisone, azathioprine, methotrexate and immunogold preparations; and biological adjuvants such as the chimeric murine-human anti-tumor necrosis (TNF) antibodies Infliximab, Adalimumab and Certolizumab; and the Integrin antibody Natalizumab, will be added to the treatment protocol [ 8 20 24 ].…”

“…Identifying biomarkers associated with different pathogenic and/or progressive stages in inflammatory bowel disease in humans has been difficult in part because of great variability in the contribution of underlying mechanisms to disease incidence, and in disease onset, progression, and remission over time [ 21 ]. It is also not unusual for severely affected IBD patients to experience multiple abdominal surgeries to remove adhesions, obstructions, strictures and chronic inflammatory material debridement [ 20 ]. Experimental genetically modified transgenic animals are important model system applications in determining disease causation, identifying potential therapeutic targets, and piloting measures contributing to alleviation of pain and distress in model systems.…”

Immunoinflammatory responses in gastrointestinal tract injury and recovery.

“…They induce formation of adducts to DNA, generate point mutations in genes like the tumor suppressor gene TP53, which is mutated early in ulcerative colitis inflamed mucosa. Increase in the local concentration of proinflammatory cytokines and prostaglandins leads to inhibition of apoptosis, favors cell proliferation and thus promotes carcinogenesis (Reimund et al, 2012)…”