Evaluation of a selective prostaglandin E receptor EP1 antagonist for potential properties in colon carcinogenesis.
BACKGROUND
Cyclooxygenases (COXs) and prostanoids play pivotal roles in colon carcinogenesis. This study was designed to determine the chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP1 antagonist, on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats and to compare its potential with that of nimesulide, a well-documented selective COX-2 inhibitor.


METHODS
Five-week-old male F344 rats received s.c. injections of AOM (15 mg/kg body weight) or the saline vehicle once weekly for two weeks and were fed the control diet (AIN-76A) or the experimental diets containing 400 or 800 ppm of ONO-8711 or 400 ppm nimesulide for 5 weeks.


RESULTS
Administration of ONO-8711 at 800 ppm significantly reduced the total number of ACF/colon and 5-bromodeoxyuridine (BrdUrd) labeling index as compared to the control diet group (by 31% and 66%, respectively). As expected, dietary administration of nimesulide also suppressed the development of ACF and BrdUrd labeling index in the colon, by about 39% and 54%, respectively.


CONCLUSIONS
Our finding that ONO-8711 significantly suppresses colonic ACF formation and cell proliferation strengthens the hypothesis that the selective prostaglandin E receptor EP1 antagonists possesses chemopreventive activity against colon cancer development.
Kawamori
T
T
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan. tkawamor@gan2.ncc.go.jp
Uchiya
N
N
Kitamura
T
T
Ohuchida
S
S
Yamamoto
H
H
Maruyama
T
T
Sugimura
T
T
Wakabayashi
K
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane / Q000037:antagonists & inhibitors / Q000633:toxicity; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002208:Caproates / Q000494:pharmacology*; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D011916:Rats, Inbred F344; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D001643:Bridged Bicyclo Compounds; D002208:Caproates; D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; C122148:ONO 8711; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D001397:Azoxymethane; C012655:nimesulide