Carcinogenesis Advance Access originally published online on May 6, 2009
Carcinogenesis 2009 30(7):1217-1224; doi:10.1093/carcin/bgp113
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5-Aminosalicylic acid inhibits colitis-associated but not sporadic colorectal neoplasia in a novel conditional Apc mouse model
Department of Gastroenterology-Hepatology
1 Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
* To whom correspondence should be addressed. Department of Gastroenterology-Hepatology, Leiden University Medical Center, C4-P, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel: +31 71 526 2680; Fax: +31 71 524 8115; Email: H.W.Verspaget{at}lumc.nl
Genetic predisposition, life-style habits and inflammatory bowel diseases (IBD)-related colitis are a main risk factor for colorectal cancer (CRC). 5-Aminosalicylic acid (5-ASA, mesalazine) is a mainstay therapy in IBD and believed to reduce the risk for developing CRC. We aimed to determine the ability of 5-ASA enemas to inhibit the development of sporadic and colitis-related neoplasia in mice. FabplCre;Apc15lox/+ mice, which spontaneously develop sporadic colorectal tumours, were treated at 5 weeks of age with 5-ASA or placebo enemas for 3 weeks and examined for colorectal tumourigenesis at 8 weeks of age. Colitis-related tumour development was investigated in these mice by administration of dextran sodium sulphate, inducing intestinal inflammation and accelerating colorectal tumourigenesis, combined with treatment of 5-ASA or placebo enemas during and/or after colitis induction. 5-ASA significantly reduced colitis-accelerated neoplasia development by 50%, from 19.4 ± 2.7 to 9.4 ± 2.4 (mean tumour numbers ± SEM, P = 0.02), in the distal part of the large intestine covered by the enema. 5-ASA was only effective when given during and/or after the intestinal inflammatory period. 5-ASA did not reduce, however, sporadic neoplasia development in the FabplCre;Apc15lox/+ mice. 5-ASA tended to reduce proliferation of epithelial cells in the colitis-associated colorectal tumours but not in the sporadic colorectal tumours. In conclusion, 5-ASA medication inhibits the development of colitis-associated tumours in FabplCre;Apc15lox/+ mice when administered during and/or after the induction of inflammation. 5-ASA does not reduce, however, sporadic tumour development in this mouse model.
Abbreviations: Apc, adenomatous polyposis coli; 5-ASA, 5-aminosalicylic acid; CRC, colorectal cancer; DAI, disease activity index; DSS, dextran sodium sulphate; IBD, inflammatory bowel disease; min, multiple intestinal neoplasia; PBS, phosphate-buffered saline; RT, room temperature; UC, ulcerative colitis
Received January 22, 2009; revised April 28, 2009; accepted April 29, 2009.