Chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP(1) antagonist, on breast cancer development.
Levels of prostaglandin E(2) (PGE(2)) in human and rodent breast cancers are higher than surrounding normal tissues. PGE(2) exhibits biological activity through binding to membrane receptors, EP(1-4). The present study was designed to investigate the effects of ONO-8711, a newly synthesized selective PGE receptor EP(1) antagonist, on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced breast cancer development. Starting at 7 weeks of age, female Sprague-Dawley (SD) rats were given PhIP (85 mg/kg body weight) by gavage four times weekly for two weeks. Dietary administration of ONO-8711 at 400 or 800 p.p.m. delayed occurrence of breast tumors for 2 or 4 weeks, respectively. At 20 weeks after the last dosing of PhIP, all animals were killed and complete autopsy was made. All breast tumors were diagnosed as invasive ductal adenocarcinomas histopathologically. Administration of ONO-8711 at 800 p.p.m. significantly decreased PhIP-induced breast cancer incidence, multiplicity and volume compared with those of rats fed the control diet (56% versus 79%, P < 0.05, 1.2 versus 2.5, P < 0.05, 0.7 versus 1.4 cm(3), P < 0.01, respectively). Apoptosis was significantly increased in breast cancer cells by feeding of ONO-8711 at 800 p.p.m. of 158% (P < 0.05). EP(1) receptor was detected by reverse transcription-polymerase chain reaction (RT-PCR) in breast cancers, not in normal tissues. These results suggest that EP(1) receptor is associated with breast cancer development and selective PGE receptor EP(1) antagonists may possess chemopreventive effects through the induction of apoptosis without any side effects.
Kawamori
T
T
Cancer Prevention Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045. tkawamor@gan2.ncc.go.jp
Uchiya
N
N
Nakatsugi
S
S
Watanabe
K
K
Ohuchida
S
S
Yamamoto
H
H
Maruyama
T
T
Kondo
K
K
Sugimura
T
T
Wakabayashi
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D002208:Caproates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype
D001643:Bridged Bicyclo Compounds; D002208:Caproates; D002273:Carcinogens; D007093:Imidazoles; C122148:ONO 8711; C545635:PTGER1 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine