title: Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).
abstract: Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effects of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc delta716 knockout mice, a model of human familial adenomatous polyposis. A Ptgs2 null mutation reduced the number and size of the intestinal polyps dramatically. Furthermore, treating Apc delta716 mice with a novel COX-2 inhibitor reduced the polyp number more significantly than with sulindac, which inhibits both isoenzymes. These results provide direct genetic evidence that COX-2 plays a key role in tumorigenesis and indicate that COX-2-selective inhibitors can be a novel class of therapeutic agents for colorectal polyposis and cancer.
authors.affiliation: Banyu Tsukuba Research Institute (Merck), Okubo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Oshima
authors.forename: J E
authors.initials: JE
authors.lastname: Dinchuk
authors.forename: S L
authors.initials: SL
authors.lastname: Kargman
authors.forename: H
authors.initials: H
authors.lastname: Oshima
authors.forename: B
authors.initials: B
authors.lastname: Hancock
authors.forename: E
authors.initials: E
authors.lastname: Kwong
authors.forename: J M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: J F
authors.initials: JF
authors.lastname: Evans
authors.forename: M M
authors.initials: MM
authors.lastname: Taketo
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000502:physiology; D005260:Female; D005663:Furans / Q000494:pharmacology*; D018628:Gene Dosage; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D017491:Genes, APC / Q000502:physiology*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology; D013997:Time Factors
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D005663:Furans; D007527:Isoenzymes; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D013467:Sulindac; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases