Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).
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.
Oshima
M
M
Banyu Tsukuba Research Institute (Merck), Okubo, Japan.
Dinchuk
J E
JE
Kargman
S L
SL
Oshima
H
H
Hancock
B
B
Kwong
E
E
Trzaskos
J M
JM
Evans
J F
JF
Taketo
M M
MM
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
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