Effects of heterocyclic amines with mammary gland carcinogenic potential on estrogenic response of uterus in ovariectomized rats.

Heterocyclic amines (HCAs) present in cooked foods are suggested to be involved in human breast cancer development. Estrogen plays a pivotal role in mammary gland carcinogenesis. Therefore, we designed an in vivo experiment to investigate potential estrogenic effects of two HCAs, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which induce mammary gland cancers in rodents, on the uterus of ovariectomized (OVX) Sprague-Dawley (SD) rats. Female SD rats ovariectomized at 35 days of age were given intraperitoneal injections of 17beta-estradiol (E2) at doses of 0, 30 or 50 microg/kg or one of the HCAs at a dose of 50 mg/kg b.w. once a day at 47, 48, and 49 days of age. E2 dramatically increased uterine weights, stromal thickness, epithelial cell height, and 5-bromo-2'-deoxyuridine (BrdU) positive cell counts in a dose dependent manner. Intraperitoneal administration of PhIP or IQ, in contrast, did not produce any estrogenic responses in this assay system. These results indicate that the carcinogenicities of these two HCAs in mammary glands are not associated with estrogenic potential.

Induction of liver preneoplastic lesions by aminophenylnorharman, formed from norharman and aniline, in male F344 rats.

9-(4'-Aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), produced by the reaction of norharman with aniline in the presence of S9 mix, is a novel heterocyclic amine (HCA), with mutagenicity to Salmonella typhimurium TA 98 and YG 1024 comparable to that of other HCAs such as 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). This experiment was designed to investigate its potential to induce glutathione S-transferase placental form (GST-P) positive foci in the liver. Male F344 rats, 7 weeks old, were fed diet containing 0, 10, 20, or 50 ppm APNH for 4 weeks, killed by ether euthanasia and performed complete necropsy. Numbers of GST-P positive foci larger than 0.1 mm in diameter induced by APNH at the dose of 10, 20, and 50 ppm were increased in a dose dependent manner to 0.52, 1.3, and 21 foci/cm2, respectively, with areas of 0.006, 0.01, and 2.3 mm2/cm2. No such GST-P positive foci were observed in rats fed control diet. These findings suggest that APNH has hepatocarcinogenic potential in male F344 rats.

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. MATERIALS AND 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. CONCLUSION: 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.

Development of micromachining technology in ion microbeam system at TIARA, JAEA.

An ion-beam-lithography technique has been progressed in the microbeam systems at Japan Atomic Energy Agency (JAEA) Takasaki. In order to obtain a high-precision measure for microbeam size estimation with a high precision, we applied this technique combined with the electroplating process to make a Ni relief pattern as a resolution standard used in secondary electron imaging. As a result, the smallest beam size could be recorded. The scattering of ions in the materials influenced the spatial resolution and this is also discussed.

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.