Inhibitory effect of etodolac, a selective cyclooxygenase-2 inhibitor, on stomach carcinogenesis in Helicobacter pylori-infected Mongolian gerbils

Magari, Hirohito; Shimizu, Yasuhito; Inada, Ken Ichi; Enomoto, Shotaro; Tomeki, Tatsuji; Yanaoka, Kimihiko; Tamai, Hideyuki; Arii, Kenji; Nakata, Hajime; Oka, Masashi; Utsunomiya, Hirotoshi; Tsutsumi, Yutaka; Tsukamoto, Tetsuya; Tatematsu, Masae; Ichinose, Masakazu

doi:10.1016/j.bbrc.2005.06.132

Cited by 34 publications

(40 citation statements)

References 40 publications

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“…These results are in line with the results of our previous animal experiment using H. pylori-infected Mongolian gerbils, 19 indicating that etodolac can prevent stomach carcinogenesis involving the CAGmetaplasia-dysplasia-cancer sequence. Essentially, the same results have also been reported with the use of another selective COX-2 inhibitor, celecoxib.…”

Section: Discussionsupporting

confidence: 91%

“…16,17 Furthermore, selective inhibition of COX-2 has been shown to prevent the progression of premalignant gastric lesions 18 and the development of gastric cancer in H. pyloriinfected Mongolian gerbils. 19,20 Treatment with COX-2 inhibitors thus appears to have beneficial preventive effects on H. pylori-associated stomach carcinogenesis. We conducted a prospective follow-up study in a group of patients with metaplastic gastritis who underwent endoscopic resection for early gastric cancer to determine whether administration of etodolac, a selective COX-2 inhibitor, prevents metachronous gastric cancer development.…”

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confidence: 99%

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Preventive effects of etodolac, a selective cyclooxygenase‐2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori‐negative precancerous lesion

Yanaoka

Oka

Yoshimura

et al. 2009

Intl Journal of Cancer

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The present study investigated the preventive effects of etodolac, a selective cyclo-oxygenase (COX)-2 inhibitor, on metachronous cancer development after endoscopic resection of early gastric cancer. Among 267 early gastric cancer patients who underwent endoscopic resection, 47 patients with extensive metaplastic gastritis were selected based on endoscopic findings and our previously described criteria of serum pepsinogen (PG) test-positive and Helicobacter pylori antibodynegative conditions. Nonrandomized etodolac treatment (300 mg/day) was administered to 26 patients (Group A), while the remaining 21 patients were untreated (Group B). No significant differences in age, sex distribution, lifestyle factors or extent of metaplastic gastritis at baseline were identified between groups. Patients were followed for metachronous cancer development with endoscopy every 6-12 months for up to 5 years. Mean (standard deviation) follow-up period was 4.2 (0.9) years. In Group B, 5 cancers developed (incidence rate 5 6,266/100,000 person-years), significantly more than the 1 cancer in Group A (incidence rate 5 898/100,000 person-years; p < 0.05). Long-term etodolac treatment did not influence the extent of metaplastic gastritis as revealed by endoscopic findings or by serum PG levels, but effectively reduced metachronous cancer development in patients with extensive metaplastic gastritis. These results strongly suggest that chemoprevention of cancer in the metaplastic stomach is possible by controlling COX-2 expression.Helicobacter pylori triggers chronic inflammation of the infected stomach mucosa and is considered a major risk factor for gastric cancer and associated precursor lesions. 1 As postulated in the multistep model of gastric cancer development by Correa, long-lasting inflammation in the stomach mucosa leads to a cascade of molecular and morphological changes of stomach carcinogenesis, representing the gastritisatrophy-metaplasia-dysplasia-cancer sequence. 2 This sequence of stomach carcinogenesis is now widely accepted to be strongly promoted by H. pylori and is affected by a variety of genetic and environmental factors that may act synergistically. 3 H. pylori eradication thus appears to be the most promising approach for the control of gastric cancer development, and the results of animal experiments have revealed that eradication of H. pylori, especially in the early stage, is effective for preventing stomach carcinogenesis. [4][5][6] However, current data indicate that H. pylori eradication does not lead to complete eradication of gastric cancer 7-12 and might be effective only in subjects without chronic atrophic gastritis (CAG) together with intestinal metaplasia. 7,10 Moreover, patients with extensive intestinal metaplasia-that is, metaplastic gastritis-should not be treated with eradication

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Preventive effects of etodolac, a selective cyclooxygenase‐2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori‐negative precancerous lesion

Yanaoka

Oka

Yoshimura

et al. 2009

Intl Journal of Cancer

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“…In epidemiologic and animal studies, long-term use of aspirin or other NSAIDs has been reported to decrease GC risk in a dose-dependent manner (Duan et al, 2008;Hu et al, 2004;Wang et al, 2003). In a Mongolian gerbil model of chronic active gastritis, which closely resembles HP-related chronic gastritis in humans, we evaluated the effects of etodolac, a selective COX-2 inhibitor, after initiation with a low dose of N-methyl-N-nitrosourea, a chemical carcinogen (Magari et al, 2005). The results confirmed that treatment with etodolac early in HP infection completely inhibited gastric carcinogenesis, which usually occurs at a high rate.…”

Section: Chemoprevention Of Gc By Nsaidsmentioning

confidence: 99%

Gastric Cancer Risk Diagnosis and Prevention in Subjects with Helicobacter pylori-related Chronic Gastritis

Enomoto¹,

Watanabe²,

Mukoubayashi³

et al. 2011

Gastritis and Gastric Cancer - New Insights in Gastroprotection, Diagnosis and Treatments

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GC risk diagnosis based on the natural history of HP-related chronic gastritisNovel risk markers to identify GC high-risk groups based on a detailed natural history of HP-related chronic gastritis have long been awaited. In this section, we discuss the emerging significance of serum PG as a GC risk marker for more precise identification of GC high-risk groups. Serum PG testHP-related chronic gastritis usually starts in the antrum and expands proximally towards the body of the stomach (Kimura, 1972;Tatsuta et al., 1973). As several studies dealing with endoscopic biopsies or chromoendoscopic testing have found that progression of chronic atrophic gastritis (CAG) increases the risk of cancer (Meister et al., 1979;Sipponen et al., 1985;Siurala et al., 1966;Tatsuta et al., 1993;Testoni et al., 1987), accurate and reliable evaluation of the extent of CAG is considered important for identifying individuals at high risk of cancer. However, accurately diagnosing the extent of CAG based on a few biopsy samples is difficult, because CAG together with intestinal metaplasia is a multifocal process. Furthermore, histological diagnosis of gastric atrophy depends on subjective judgment without a gold standard (Guarner et al., 1999;Plummer et al., 1997). A test for CAG progression that is more convenient, free of discomfort or risk, economical and based on objective parameters is needed. PG is the inactive precursor of pepsin, a digestive enzyme specifically produced in the stomach. Immunologically, two isozymes exist (Kageyama, 2003). PGI is produced by chief cells and mucus neck cells of the gastric fundic glands. In contrast, PGII is produced not only by chief cells and mucus neck cells, but also in cardiac glands, pyloric glands, and Brunner's glands, with localization of producing cells in a wide range from the stomach to the duodenum. The majority of PG produced (about 99%) is secreted in the stomach lumen and functions as a digestive enzyme. However, a small amount of PG (about 1%) is also present in blood and can be evaluated by measuring serum PG levels. Serum PG levels are generally agreed to reflect the morphological and functional status of the stomach mucosa (Hirschowitz, 1957;Samloff et al., 1982). In an endoscopic study with Congo red staining, we have shown a strong correlation between an increase in glandular boundary, associated with diagnosed progression of gastric mucosal atrophy, and stepwise reductions in serum PGI levels and the PGI/PGII ratio ( Fig. 1) (Miki et al., 1987). In other words, by measuring serum PGI and the PGI/II ratio, the progression of CAG, which is involved in GC carcinogenesis, can be objectively evaluated (Ichinose et al., 2001). In addition, during HP infection, serum PGI and PGII increase, and the PG I/II ratio decreases. These findings are improved after eradication treatment (Furuta et al., 1997) and are useful as gastric mucosal inflammatory markers. Several criteria are used in the serum PG test. As criteria for GC screening, the combination of PGI ≤70 ng/ml and PGI/II ratio ≤3.0...

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“…Serum samples were also centrifuged (4°C, 10,000g for 30 min) through centrifugal filter devices (Microcon YM-10, Millipore, Bedford, MA) and measured for 8-OHdG levels (ELISA; high sensitive 8-OHdG check; Japan Institute for Control of Aging, Shizuoka, Japan). 21 …”

Section: Analysis Of Mrna Expression Of Cytokines By Real Time Quantimentioning

confidence: 99%

4‐Vinyl‐2,6‐dimethoxyphenol (canolol) suppresses oxidative stress and gastric carcinogenesis in Helicobacter pylori‐infected carcinogen‐treated Mongolian gerbils

Cao

Tsukamoto

Seki

et al. 2008

Intl Journal of Cancer

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Oxidative stress is linked to gastric carcinogenesis because of its ability to damage DNA. Here we examined antioxidative and antiinflammatory effects of 4-vinyl-2,6-dimethoxyphenol (canolol), a recently identified potent antioxidative compound obtained from crude canola oil, on Helicobacter (H.) pylori-induced gastritis and gastric carcinogenesis using a Mongolian gerbil model. The animals were allocated to H. pylori-infection alone (12 weeks) or H. pylori 1 N-methyl-N-nitrosourea (MNU) administration (52 weeks). After oral inoculation of H. pylori, they were fed for 10 and 44 weeks with or without 0.1% canolol. H. pylori-induced gastritis, 5 0 -bromo-2 0 -deoxyuridine (BrdU) labeling and scores for cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) immunohistochemistry were attenuated in the canololtreated groups. Expression of interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), COX-2 and iNOS mRNA in the gastric mucosa, and serum 8-hydroxy-2 0 -deoxyguanosine (8-OHdG), anti-H. pylori IgG and gastrin levels were also significantly lower in canolol-treated groups. Furthermore, the incidence of gastric adenocarcinomas was markedly reduced in the H. pylori 1 MNU 1 canolol-treated group [15.0% (6/40)] compared to the control group [39.4% (13/33)] (p < 0.05). These data indicate canolol to be effective for suppressing inflammation, gastric epithelial cell proliferation and gastric carcinogenesis in H. pylori-infected Mongolian gerbils. Interestingly, the viable H. pylori count was not changed by the canolol containing diet. Thus, the data point to the level of inflammation because of H. pylori rather than the existence of the bacteria as the determining factor. Importantly, canolol appears to suppress induction of mRNAs for inflammatory cytokines. ' 2007 Wiley-Liss, Inc.

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Inhibitory effect of etodolac, a selective cyclooxygenase-2 inhibitor, on stomach carcinogenesis in Helicobacter pylori-infected Mongolian gerbils

Cited by 34 publications

References 40 publications

Preventive effects of etodolac, a selective cyclooxygenase‐2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori‐negative precancerous lesion

Preventive effects of etodolac, a selective cyclooxygenase‐2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori‐negative precancerous lesion

Gastric Cancer Risk Diagnosis and Prevention in Subjects with Helicobacter pylori-related Chronic Gastritis

4‐Vinyl‐2,6‐dimethoxyphenol (canolol) suppresses oxidative stress and gastric carcinogenesis in Helicobacter pylori‐infected carcinogen‐treated Mongolian gerbils

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