Cyclooxygenase (COX)-2 has been suggested to play an important role in colon carcinogenesis. We found that the COX-2 selective inhibitor, nimesulide, reduces azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rats and colon carcinogenesis in mice, as well as formation of intestinal polyps in Min mice. Thus, selective inhibitors of COX-2, which catalyzes the synthesis of prostanoids, could be good candidates as chemopreventive agents against colon cancer. Examination of the effect of prostanoid receptor deficiency and a selective antagonist of prostanoid receptor on the development of AOM-induced ACF in mice revealed the involvement of the EP1 receptor. Moreover, a selective EP1 antagonist reduced the number of intestinal polyps in Min mice. These results suggest that PGE2 contributes to colon carcinogenesis through binding to the EP1 receptor. Nitric oxide synthase (NOS) is known to be overexpressed in colon cancers of humans and rats, and a NOS inhibitor, L-NG-nitroarginine methyl ester, was found to inhibit the development of AOM-induced ACF in rats. Thus, NOS including iNOS could also be a good target for chemoprevention of colon cancer, as in the COX-2 case.

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Breast cancer is common in women all over the world, and exploration of chemopreventive approaches to this cancer is very important. Nimesulide, a selective inhibitor of cyclooxygenase-2 (COX-2), is a good candidate as a chemopreventive agent with low toxicity. We examined its effects on mammary tumor development in female Sprague-Dawley rats induced with the environmental carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Rats at 7 weeks of age received intragastric intubations of PhIP (85 mg/kg body weight) 4 times weekly for 2 weeks and were maintained on control diet (high fat diet) or experimental diet (high fat diet supplemented with 400 ppm nimesulide) throughout the experiment. COX-2 protein was over-expressed in epithelial cancer cells and stromal cells of the PhIP-induced mammary carcinomas, but was weak or not apparent in normal mammary gland cells. The development of mammary carcinomas was clearly suppressed by administration of nimesulide. The carcinoma incidence was 51% as compared to 71% for the control diet group. The average multiplicity of carcinomas in the experimental diet group was 1.2 ± ± ± ±0.2 (P < < < <0.05), significantly smaller than the control diet group value (2.6 ± ± ± ±0.5). The size of carcinomas was also clearly decreased; 1.1 ± ± ± ±0.4 cm 3 /rat in experimental diet group (P < < < <0.05), 4.1 ± ± ± ±1.3 cm 3 /rat in the control diet group. The results therefore provide evidence that the selective COX-2 inhibitor, nimesulide, possesses chemopreventive activity against PhIPinduced mammary carcinogenesis in rats.Key words: Nimesulide -COX-2 inhibitor -Chemoprevention -Mammary gland cancer -PhIP Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to decrease prostanoid synthesis through inhibition of cyclooxygenase (COX) activity, 1) resulting in antiinflammatory effects. Two isoforms of cyclooxygenase-1 and -2 (COX-1 and COX-2) have been characterized in mammalian and avian species. COX-1 is constitutively expressed in most tissues to regulate prostaglandin (PG) production and maintain stable physiological conditions, including gastric cytoprotection and blood flow. In contrast, COX-2 is transiently induced by lipopolysaccharide, cytokines and growth factors, and has been indicated to produce large amount of prostanoids involved in inflammation and mitogenesis.2) COX-2 protein and mRNA are known to be expressed in not only inflammatory tissues, but also colorectal cancers in rats and humans.3, 4) Consistent with a causal role, regular use of aspirin has been shown to lower the risk of colon cancer in man. 5) Animal model studies have also demonstrated that NSAIDs, including aspirin and sulindac, can suppress colon carcinogenesis induced by azoxymethane (AOM) in rats.6, 7) In addition, NSAIDs have been shown to inhibit chemically induced mammary carcinogenesis in rats. 8, 9) Conventional NSAIDs such as aspirin, sulindac and indomethacin block both COX-1 and COX-2, resulting in unwanted side effects such as gastritis and gastric ulceration. However, selective CO...

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.

These data suggested that establishment of a suitable biomarker panel would facilitate detection of site-specific kidney injury with high sensitivity.

The present study suggests that ombitasvir/paritaprevir/ritonavir combination therapy is effective and safe for genotype 1b chronic hepatitis C patients undergoing dialysis due to ESRD.

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Background In April 2017, we launched the multidisciplinary Hamamatsu Perioperative Care Team (HOPE) for all surgical patients. We developed a reinforced intervention strategy, particularly for esophagectomy. We herein report the outcomes of the HOPE at 2 years after commencement. Methods A total 125 patients underwent esophagectomy and gastric conduit reconstruction for esophageal or esophagogastric junction cancer between January 2014 and December 2018 at the Department of Surgery in Hamamatsu University School of Medicine. The patients were divided into the pre-HOPE group including 62 patients who underwent esophagectomy before the introduction of the HOPE and the HOPE group including 63 patients who underwent esophagectomy after the introduction of the HOPE. The outcomes of surgery were compared between the two groups. Results There were no significant differences in the clinicopathological characteristics between the two groups. The incidence rates of atrial fibrillation and pneumonia were significantly lower in the HOPE group than in the pre-HOPE group (6% vs. 19%, p = 0.027 and 14% vs. 29%, p = 0.037, respectively). The estimated calorie doses at the time of discharge were approximately 750 and 1500 kcal/day in the pre-HOPE group and the HOPE group, respectively. The body weight loss was significantly less in the HOPE group than the pre-HOPE group at 1, 3, 6, and 12 months postoperatively than that before the surgery (p < 0.001). Conclusions The introduction of the multidisciplinary HOPE was associated with a significant reduction in the incidence of postoperative pneumonia and significantly less weight loss.