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.
MeSH terms
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Adenomatous Polyposis Coli / drug therapy
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Adenomatous Polyposis Coli / enzymology*
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Adenomatous Polyposis Coli / genetics
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Adenomatous Polyposis Coli Protein
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Animals
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Cytoskeletal Proteins / genetics*
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Extracellular Space / physiology
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Female
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Furans / pharmacology*
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Gene Dosage
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Gene Expression Regulation, Enzymologic / physiology
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Gene Expression Regulation, Neoplastic / physiology
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Genes, APC / physiology*
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Intestinal Mucosa / enzymology
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Intestinal Mucosa / pathology
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Isoenzymes / drug effects
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Isoenzymes / genetics*
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Isoenzymes / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutagenesis / physiology
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Prostaglandin-Endoperoxide Synthases / drug effects
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Prostaglandin-Endoperoxide Synthases / genetics*
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Prostaglandin-Endoperoxide Synthases / metabolism
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Sulindac / pharmacology
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Time Factors
Substances
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Adenomatous Polyposis Coli Protein
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Cytoskeletal Proteins
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Enzyme Inhibitors
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Furans
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Isoenzymes
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3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone
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Sulindac
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases