Reference Detail

Ref Type

Journal Article

PMID

(19755659)

Authors

Itano O, Yang K, Fan K, Kurihara N, Shinozaki H, Abe S, Jin B, Gravaghi C, Edelmann W, Augenlicht L, Kopelovich L, Kucherlapati R, Lamprecht S, Lipkin M

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Carcinogenesis	30	11	2009 Nov	1923-6	Carcinogenesis

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Sulindac	Sulindac	7	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Sulindac	Clinoril	MK-231		Clinoril (sulindac) is a non-selective COX1-2 inhibitor, FDA approved as an anti-inflammatory agent (FDA.gov), and Clinoril (sulindac) also reduces intestinal tumor burden (PMID: 19755659).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
APC inact mut	colorectal cancer	sensitive	Sulindac	Preclinical	Actionable	In a preclinical study, colorectal cancer mouse models carrying APC inactivating mutations had reduced intestinal tumor burden after treatment with Clinoril (sulindac) (PMID: 19755659).	19755659