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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.
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