Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations.

Carcinogenesis 2009 Nov 15;30(11):1923-6. Epub 2009 Sep 15.

Strang Cancer Research Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.

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 Apc(Min/+) 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) Apc(1638N/+) 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(+/-)Apc(1638N/+) 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 Apc(1638N/+) mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1(+/-)Apc(1638N/+) 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 Apc(1638N/+) mice, but it increased inflammation in the small intestine of Mlh1(+/-) mice and Mlh1(+/-)Apc(1638N/+) 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.

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgp200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783002PMC
November 2009
32 Reads

Publication Analysis

Top Keywords

small intestine
20
mutant mice
12
increased tumors
12
mice
11
sulindac
10
intestine apc1638n/+
8
apc1638n/+ mice
8
intestinal regional
8
inhibited tumor
8
mouse models
8
effects sulindac
8
genetic background
8
inflammation small
8
mutant mouse
8
model human
8
mlh1+/-apc1638n/+ mutant
8
sulindac increased
8
intestine
7
mouse
6
mutant
5

References

(Supplied by CrossRef)

Similar Publications