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Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis.

Abstract
Although the cyclooxygenase pathway of the arachidonic acid cascade has been suggested to play an important role in colon carcinogenesis, the molecular species of prostanoids and receptors involved have not been fully elucidated yet. We examined the development of aberrant crypt foci (ACFs), putative preneoplastic lesions of the colon, in two lines of knockout mice, each deficient in prostaglandin E receptors, EP1 and EP3, by treatment with the colon carcinogen, azoxymethane. Formation of ACFs was decreased only in the EP1-knockout mice to approximately 60% of the level in wild-type mice. Administration of 250, 500, or 1000 ppm of a novel selective EP1 antagonist, ONO-8711, in the diet to azoxymethane-treated C57BL/6J mice also resulted in a dose-dependent reduction of ACF formation. Moreover, when Min mice, having a nonsense mutation in the adenomatous polyposis coli gene, were given 500 ppm ONO-8711 in the diet, the number of intestinal polyps was significantly reduced to 57% of that in the basal diet group. These results strongly suggest that prostaglandin E2 contributes to colon carcinogenesis to some extent through its action at the EP1 receptor. Thus, EP1 antagonists may be good candidates as chemopreventive agents for colon cancer.
AuthorsK Watanabe, T Kawamori, S Nakatsugi, T Ohta, S Ohuchida, H Yamamoto, T Maruyama, K Kondo, F Ushikubi, S Narumiya, T Sugimura, K Wakabayashi
JournalCancer research (Cancer Res) Vol. 59 Issue 20 Pg. 5093-6 (Oct 15 1999) ISSN: 0008-5472 [Print] United States
PMID10537280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Bridged Bicyclo Compounds
  • Caproates
  • ONO 8711
  • Ptger1 protein, mouse
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype
  • Azoxymethane
Topics
  • Animals
  • Azoxymethane (toxicity)
  • Bridged Bicyclo Compounds (pharmacology)
  • Caproates (pharmacology)
  • Colonic Neoplasms (etiology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Precancerous Conditions (etiology)
  • Receptors, Prostaglandin E (antagonists & inhibitors, physiology)
  • Receptors, Prostaglandin E, EP1 Subtype

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