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.

• Authors: Naoko Niho, Michihiro Mutoh, Tomohiro Kitamura, Mami Takahashi, Hidetaka Sato, Hiroshi Yamamoto, Takayuki Maruyama, Shuichi Ohuchida, Takashi Sugimura, Keiji Wakabayashi
• Journal: Cancer science (Cancer Sci) Vol. 96 Issue 5 Pg. 260-4 (May 2005) ISSN: 1347-9032 [Print] England
• PMID: 15904466 (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
• Apoptosis (drug effects)
• Azoxymethane (pharmacology)
• Bridged 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