Journal Article

Chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP<sub>1</sub> antagonist, on breast cancer development

Toshihiko Kawamori, Naoaki Uchiya, Seiichi Nakatsugi, Kouji Watanabe, Shuichi Ohuchida, Hiroshi Yamamoto, Takayuki Maruyama, Kigen Kondo, Takashi Sugimura and Keiji Wakabayashi

in Carcinogenesis

Volume 22, issue 12, pages 2001-2004
Published in print December 2001 | ISSN: 0143-3334
Published online December 2001 | e-ISSN: 1460-2180 | DOI:
Chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP1 antagonist, on breast cancer development

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  • Clinical Cytogenetics and Molecular Genetics


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Levels of prostaglandin E2 (PGE2) in human and rodent breast cancers are higher than surrounding normal tissues. PGE2 exhibits biological activity through binding to membrane receptors, EP1–4. The present study was designed to investigate the effects of ONO-8711, a newly synthesized selective PGE receptor EP1 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 cm3, 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). EP1 receptor was detected by reverse transcription-polymerase chain reaction (RT-PCR) in breast cancers, not in normal tissues. These results suggest that EP1 receptor is associated with breast cancer development and selective PGE receptor EP1 antagonists may possess chemopreventive effects through the induction of apoptosis without any side effects.

Keywords: AgNOR, silver-stained nucleolar organizer region protein; COX, cyclooxygenase; ISEL, in situ end-labeling of fragmented DNA; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; RT-PCR, reverse transcription-polymerase chain reaction; SD, Sprague–Dawley

Journal Article.  3343 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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