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Suppression of azoxymethane-induced colon cancer development in rats by a prostaglandin E receptor EP1-selective antagonist.

Abstract
Prostaglandin E(2) is involved in colon carcinogenesis through its binding to the PGE(2) receptor subtypes EP(1), EP(2), EP(3) and EP(4). We have demonstrated that administration of ONO-8711, an EP(1)-selective antagonist, suppresses development of AOM-induced ACF in C57BL/6 mice and F344 rats. ONO-8711 also reduced the numbers of intestinal polyps in Min mice. In the present study, we investigated the long-term effects of ONO-8711 on colon cancer development in rats treated with AOM. Male F344 rats were injected subcutaneously with AOM (15 mg/kg body weight) once a week for the first 2 weeks to develop colon cancer. Administration of 400 or 800 p.p.m. ONO-8711 in their diets for 32 weeks reduced the incidence, multiplicity and volume of colon carcinomas. The incidence of colon adenocarcinomas in AOM-treated rats was 97, 83 and 76% (P < 0.05) in the 0, 400 and 800 p.p.m. of ONO-8711 groups, respectively. The multiplicity of adenocarcinomas was also decreased significantly, being 3.31 +/- 0.33, 2.34 +/- 0.27 (P < 0.05) and 2.06 +/- 0.34 (P < 0.01) with 0, 400 and 800 p.p.m. of ONO-8711, respectively. Moreover, treatment with 800 p.p.m. ONO-8711 reduced the mean volume of adenocarcinomas to 49% (P < 0.05) of the value for the AOM treatment alone. Furthermore, the BrdU labeling index was decreased significantly in colon cancer cells by 800 p.p.m. ONO-8711. These results confirm that EP(1) is involved in colon carcinogenesis and that EP(1)-selective antagonists might be promising candidates for colon cancer chemopreventive agents.
AuthorsNaoko Niho, Michihiro Mutoh, Tomohiro Kitamura, Mami Takahashi, Hidetaka Sato, Hiroshi Yamamoto, Takayuki Maruyama, Shuichi Ohuchida, Takashi Sugimura, Keiji Wakabayashi
JournalCancer science (Cancer Sci) Vol. 96 Issue 5 Pg. 260-4 (May 2005) ISSN: 1347-9032 [Print] England
PMID15904466 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Bicyclo Compounds
  • Caproates
  • ONO 8711
  • Ptger1 protein, mouse
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype
  • Azoxymethane
Topics
  • Animals
  • Apoptosis (drug effects)
  • Azoxymethane (pharmacology)
  • Bicyclo Compounds (pharmacology, therapeutic use)
  • Caproates (pharmacology, therapeutic use)
  • Colonic Neoplasms (chemically induced, metabolism, pathology, prevention & control)
  • Male
  • Rats
  • Rats, Inbred F344
  • Receptors, Prostaglandin E (antagonists & inhibitors, metabolism)
  • Receptors, Prostaglandin E, EP1 Subtype

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