title: Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations.
abstract: 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.
authors.affiliation: Strang Cancer Research Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Osamu
authors.initials: O
authors.lastname: Itano
authors.forename: Kan
authors.initials: K
authors.lastname: Yang
authors.forename: Kunhua
authors.initials: K
authors.lastname: Fan
authors.forename: Naoto
authors.initials: N
authors.lastname: Kurihara
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Shinozaki
authors.forename: Sadanori
authors.initials: S
authors.lastname: Abe
authors.forename: Bo
authors.initials: B
authors.lastname: Jin
authors.forename: Claudia
authors.initials: C
authors.lastname: Gravaghi
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Leonard
authors.initials: L
authors.lastname: Augenlicht
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Sergio
authors.initials: S
authors.lastname: Lamprecht
authors.forename: Martin
authors.initials: M
authors.lastname: Lipkin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D011125:Adenomatous Polyposis Coli / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D002432:Cecum / Q000187:drug effects / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D051379:Mice; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D013467:Sulindac / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D013467:Sulindac; D000070957:MutL Protein Homolog 1