Suppression of azoxymethane-induced colon cancer development in rats by a prostaglandin E receptor EP1-selective antagonist.
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.
Niho
Naoko
N
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. nniho@gan2.ncc.go.jp
Mutoh
Michihiro
M
Kitamura
Tomohiro
T
Takahashi
Mami
M
Sato
Hidetaka
H
Yamamoto
Hiroshi
H
Maruyama
Takayuki
T
Ohuchida
Shuichi
S
Sugimura
Takashi
T
Wakabayashi
Keiji
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002208:Caproates / Q000494:pharmacology* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype
D001643:Bridged Bicyclo Compounds; D002208:Caproates; C122148:ONO 8711; C545636:Ptger1 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D001397:Azoxymethane