Suppression of Intestinal Polyposis in Apc delta716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2)

Cell. 1996 Nov 29;87(5):803-9. doi: 10.1016/s0092-8674(00)81988-1.

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

  • Adenomatous Polyposis Coli / drug therapy
  • Adenomatous Polyposis Coli / enzymology*
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli Protein
  • Animals
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Cytoskeletal Proteins / genetics*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Extracellular Space / physiology
  • Female
  • Furans / pharmacology*
  • Gene Dosage
  • Gene Expression Regulation, Enzymologic / physiology
  • Gene Expression Regulation, Neoplastic / physiology
  • Genes, APC / physiology*
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / pathology
  • Isoenzymes / drug effects
  • Isoenzymes / genetics*
  • Isoenzymes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagenesis / physiology
  • Prostaglandin-Endoperoxide Synthases / drug effects
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Sulindac / pharmacology
  • Time Factors

Substances

  • Adenomatous Polyposis Coli Protein
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Furans
  • Isoenzymes
  • 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone
  • Sulindac
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases