Carcinogenesis Advance Access published online on May 6, 2009
Carcinogenesis, 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
1 Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands
2 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Correspondence: Dr. Hein W. Verspaget, MSc, PhD associate professor, Department of Gastroenterology-Hepatology, Leiden University Medical Center, C4-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands, Tel: +31715262680, Fax: +31715248115, 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 (DSS), 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.
Key Words: 5-ASA • colorectal cancer • conditional Apc mice • DSS • colitis • IBD
Received January 22, 2009; revised April 28, 2009; accepted April 29, 2009.