Carcinogenesis Advance Access originally published online on September 15, 2009
Carcinogenesis 2009 30(11):1923-1926; doi:10.1093/carcin/bgp200
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Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations
Strang Cancer Research Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA
1 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10467, USA
2 Department of Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
3 Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20852, USA
4 Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA
* To whom correspondence should be addressed. Tel: +1 212 879 9371; Fax: +1 212 794 4958; Email: mal2019{at}med.cornell.edu
We have previously reported that sulindac, a non-steroidal anti-inflammatory drug, inhibited tumor formation in the small intestine but increased tumors in the colon of ApcMin/+ mice, a model of human familial adenomatous polyposis. To further explore intestinal regional responses, we studied effects of sulindac on additional gene-targeted mouse models of human intestinal tumorigenesis; these were (i) Apc1638N/+ mouse (chain termination mutation in exon 15 of the Apc gene); (ii) Mlh1+/– mouse (DNA mismatch repair deficiency, a mouse model of human hereditary non-polyposis colorectal cancer) and (iii) double-heterozygous Mlh1+/–Apc1638N/+ mutant mouse. Mice were fed AIN-76A control diet with or without 0.02% sulindac for 6 months. Intestinal regional tumor incidence, multiplicity, volume and degree of inflammation were used as end points. The results showed the following: (i) sulindac inhibited tumor development in the small intestine of Apc1638N/+ mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1+/–Apc1638N/+ mutant mice; (iii) sulindac increased tumors in the cecum of all mice regardless of genetic background; (iv) sulindac decreased inflammation in the small intestine of Apc1638N/+ mice, but it increased inflammation in the small intestine of Mlh1+/– mice and Mlh1+/–Apc1638N/+ mice and (v) sulindac enhanced inflammation in the cecum of all mutant mice. Findings indicate that the effects of sulindac in the intestine of these mutant mouse models are probably related to genetic background and appear to be associated with its inflammatory-inducing response.
Abbreviations: FAP, familial adenomatous polyposis; NSAID, non-steroidal anti-inflammatory drug
Received April 20, 2009; revised August 10, 2009; accepted August 12, 2009.