Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the role of mitogen-inducible cyclooxygenase (COX-2) in the development of malignant tumors, we investigated the effects of COX-2 inhibitors on the growth of gastric cancer xenografts in nude mice in vivo. MKN45 gastric cancer cells (5 x 10(6) cells/animal) that overexpress COX-2 were inoculated subcutaneously into athymic mice. NS-398, a specific COX-2 inhibitor, or indomethacin, a nonspecific COX-2 inhibitor, was administered orally to animals every day for 20 days. These drugs reduced the tumor volume significantly. Immunohistochemistry using bromodeoxyuridine, nick end labeling, and electron microscopy showed that NS-398 induced apoptosis in cancer cells in a dose-dependent manner and inhibited cancer cell replication slightly. Indomethacin also induced apoptosis and suppressed replication of tumor cells. There was a significant negative correlation between tumor volume and apoptotic cell number within the tumor. These results are consistent with the hypothesis that COX-2 inhibitors suppress growth of gastric cancer xenografts mainly by inducing apoptosis and suppressing replication of the neoplastic cells. It follows that COX-2 plays an important role in the development of gastric cancer.
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PMID:Cyclooxygenase-2 inhibitors suppress the growth of gastric cancer xenografts via induction of apoptosis in nude mice. 969 6

Although recent studies have demonstrated that cyclooxygenase (COX)-2 is overexpressed in various cancers including gastric cancer, the mechanisms underlying the contribution of COX-2 to tumorigenesis and tumor promotion still remain unclear. To determine the role of COX-2, we investigated the COX-2 expression, the prostaglandin (PG) levels, and the microvessel density in 42 patients with primary gastric adenocarcinoma. COX-2 protein was over-expressed in 31 (74%) of 42 gastric cancers based on an immunoblot analysis. The intensity of COX-2 expression was found to significantly correlate with lymph node involvement. The COX-2 overexpressed cases showed significantly elevated levels of prostaglandin E2 (PGE2) in cancer tissues in comparison with the normal gastric mucosa by an immunoassay (201 +/- 90 versus 161 +/- 57 ng/mg protein; P < 0.05). However, the COX-2 overexpression was not related to the levels of thromboxane B2 and 6-keto-prostaglandin F1alpha. The density of microvessel immunostained with CD34 was significantly higher in patients demonstrating COX-2 overexpression than in those without such expression (63 +/-21 versus 45 +/- 17/200 x; P < 0.01). Our data thus suggested COX-2 overexpression to be associated with increased PGE2 biosynthesis and angiogenesis in gastric cancer, which indicates that COX-2 may play a role in the development of gastric cancer.
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PMID:Cyclooxygenase-2 expression is related to prostaglandin biosynthesis and angiogenesis in human gastric cancer. 1065 41

Gastric adenocarcinoma is one of the most common malignancies in the world, and yet little is known about its molecular process of development and progression. Recent studies have suggested that ingestion of nonsteroid anti-inflammatory drugs reduces the risk of colon cancer, presumably by inhibiting the cyclooxygenase (COX) enzyme. COX-2, one isoform of the COX enzyme, is the rate-limiting enzyme in prostaglandin synthesis, and the function of this enzyme is thought to relate to inflammatory processes and carcinogenesis. To understand the role of COX enzyme in gastric cancer, we measured COX-2 expression in 104 human gastric carcinoma tissues by immunohistochemical analysis. We obtained tissue specimens from 104 surgically resected gastric adenocarcinoma patients. We performed immunohistochemical stain for human COX-2 with polyclonal antibody in gastric carcinoma. After curative resection and extensive lymph node dissection, all patients received adjuvant chemotherapy containing 5-fluorouracil. Expression of COX-2 showed cytoplasmic staining, not only in cancer cells but also in precancerous lesions such as metaplastic and adenomatous cells. We confirmed up-regulation of COX-2 in gastric cancer tissues compared with normal paired mucosa using Western blot analysis. There was no correlation between clinicopathological characteristics of gastric cancer patients and intensity of COX-2 protein expression. This study indicates that COX-2 protein over-expression may contribute to an early event of gastric cancer development, and it further suggests that selective inhibition of COX-2 may provide a chemopreventive effect against gastric carcinogenesis.
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PMID:Increased expression of cyclooxygenase-2 protein in human gastric carcinoma. 1069 May 33

Wild-type p53 competitively binds to the promoter region of COX-2 in vitro and inhibits its transcription. We examined the association between p53 mutation and COX-2 expression in gastric cancer. COX-2 over-expression was seen in 19 (48.7%) cases. These tumours had more lymph-node metastasis (P = 0.048) and tended to have a poorer survival (P = 0.07). Missense mutations of p53 were detected in 20 (51.3%) patients and had a significantly stronger COX-2 expression than tumours without p53 mutation (P = 0.016). Our results suggest a link between p53 mutation and COX-2 overexpression in gastric cancer.
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PMID:Association between cyclo-oxygenase-2 overexpression and missense p53 mutations in gastric cancer. 1116 97

An increased expression of cyclooxygenase (COX)-2 has been observed in various cancers including gastric cancer. Although specific COX-2 inhibitors have a chemopreventive effect on colon cancer, their molecular mechanisms remain unclear. To clarify these mechanisms, we investigated the effects of JTE-522, a newly developed COX-2-specific inhibitor, on gastric cancer cell lines (MKN28 and MKN45). The baseline levels of COX-2 expression were higher in MKN45 than in MKN28. JTE-522 obviously suppressed the levels of COX-2 mRNA, COX-2 protein and PGE2 at a dose of 250 microM in both cancer cells. Apoptosis was induced at 24 hours after treatment with JTE-522 (250 microM) in both cancer cells. To determine the mechanisms of apoptosis induction by JTE-522, the time course of the cell cycle and the apoptosis-related protein levels were examined. An increase in the G1 phase and a decrease in the S phase were observed prior to apoptosis. Moreover, an increase of c-myc protein and a decrease of bcl-2 protein were observed in both cells treated with JTE-522. These findings suggested that JTE-522 could induce apoptosis by blocking the cell cycle, enhancing c-myc expression and diminishing bcl-2 expression. JTE-522 also suppressed proliferation activity in both cell lines. These effects of JTE-522 were more dramatic in MKN45 than in MKN28. Since JTE-522 strongly suppresses cell growth by inducing apoptosis in gastric cancer cell lines, it may therefore serve as a chemopreventive agent.
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PMID:Induction of apoptosis by JTE-522, a specific cyclooxygenase-2 inhibitor, in human gastric cancer cell lines. 1120 58

Cyclooxygenase (COX)-2, the inducible form of the rate-limiting enzyme for prostaglandin synthesis, is up-regulated in gastrointestinal cancers and is a key mediator of epithelial cell growth. Helicobacter pylori is causally linked to gastric cancer. In H. pylori gastritis, COX-2 expression localizes to the subepithelial region, with variable levels in the epithelium. In contrast, in gastric cancer, COX-2 strongly predominates in the epithelium, suggesting that the transition to consistent epithelial COX-2 overexpression may be a critical molecular event in gastric carcinogenesis. Because aberrant promoter methylation inhibits expression of a variety of genes in gastrointestinal cancers, we sought to determine whether methylation of the COX-2 promoter could regulate the response to H. pylori in gastric epithelial cells. We assessed COX-2 expression and promoter methylation status in six gastric epithelial cell lines. In all four of the cell lines that exhibited basal expression of COX-2 and a significant increase in expression in response to H. pylori, the COX-2 promoter was unmethylated, whereas in the two cell lines that did not express COX-2, the COX-2 promoter was methylated. Treatment of COX-2-methylated cells with the demethylating agent 5-azacytidine had a modest effect on COX-2 expression, but when 5-azacytidine-treated cells were subsequently stimulated with H. pylori, there was a significant, 5-10-fold enhancement of both COX-2 mRNA and protein expression and release of the COX-2 product, prostaglandin E2. In contrast, in COX-2-expressing cell lines that were unmethylated at the COX-2 promoter, 5-azacytidine had no effect on H. pylori-stimulated COX-2 expression. These findings suggest that loss of COX-2 methylation may facilitate COX-2 expression and promote gastric carcinogenesis associated with H. pylori infection.
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PMID:Promoter methylation regulates Helicobacter pylori-stimulated cyclooxygenase-2 expression in gastric epithelial cells. 1128 4

Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are two well-known important causative factors of gastric damage. While H. pylori increases apoptosis and the proliferation of gastric epithelial cells and is an important factor in peptic ulcer and gastric cancer, NSAIDs induce cell apoptosis and have antineoplastic effects. We investigated the effects of NSAIDs (a nonselective cyclooxygenase [COX] inhibitor [indomethacin] and a selective COX-2 inhibitor [NS-398]) on the apoptosis and proliferation of gastric epithelial cells and gastric inflammation in H. pylori-infected mice. C57BL/6 mice were sacrificed 8 weeks after H. pylori SS1 inoculation. Indomethacin (2 mg/kg) or NS-398 (10 mg/kg) was administered subcutaneously once daily for 10 days before sacrifice. The following were assessed: gastric inflammatory activity, gastric COX protein expression by Western blotting; gastric prostaglandin E(2) levels by enzyme immunoassay, apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and cell proliferation by Ki67 immunostaining. Compared to the controls, H. pylori infection and/or NSAID treatment increased COX-1 and COX-2 protein expression. Gastric prostaglandin E(2) levels, apoptotic index, cell proliferation index, neutrophil activity, and the degree of chronic inflammation were all increased by H. pylori infection, and these effects were significantly decreased by indomethacin treatment. However, NS-398 treatment after H. pylori infection did not induce a significant reduction, although it did result in a tendency to decrease. These results show that NSAIDs can reverse the increased apoptosis and proliferation of epithelial cells and inflammatory activity in the stomachs of H. pylori-infected mice and that, like COX-2 activation, COX-1 induction contributes to the change of gastric mucosal cell turnover and inflammation induced by H. pylori infection.
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PMID:Effects of nonsteroidal anti-inflammatory drugs on Helicobacter pylori-infected gastric mucosae of mice: apoptosis, cell proliferation, and inflammatory activity. 1144 86

The present study evaluated the significance of nitric oxide synthase (NOS), cyclooxygenase (COX) expression and p53 status in 55 patients with gastric adenocarcinoma and relationship of these molecular markers to tumor characteristics and metastatic potential. Immunohistochemical technique was used to identify the cellular location and distribution of the enzymes in the specific cells of gastric tumors. In gastric cancer tissue, the expression of inducible enzymes, iNOS and COX-2, increased significantly with increasing tumor stage (P=0.015, P=0.001, respectively), size (P=0.025, P=0.001, respectively) and the presence of metastases (P=0.002, P=0.015, respectively). The expression of constitutive enzymes, ecNOS and COX-1, followed the opposite pattern. COX-1 was significantly reduced in advanced gastric tumors (P=0.007) and tumors larger than 5 cm (P=0.007). Reduced expression of ecNOS was also observed in advanced gastric tumors; however, this did not reach statistical significance. 53% of gastric tumors showed accumulation of p53. This was significantly higher in advanced tumors (P=0.004), larger than 5 cm (P=0.015) with metastases (P<0.001). Gastric tumors positive for accumulation of p53 had significantly stronger expression of iNOS (P=0.018) and COX-2 (P=0.01) enzymes than tumors negative for this nucleophosphoprotein. We conclude, that tumor-associated nitric oxide production, as well as COX-2 overexpression, may promote gastric cancer progression by providing a selective growth advantage to tumor cells with non-functioning p53.
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PMID:Expression of nitric oxide synthase, cyclooxygenase, and p53 in different stages of human gastric cancer. 1156 94

Cyclooxygenase 2 plays a critical role in the development of gastrointestinal cancers in both human and animal models. About 80% of the gastric cancer showed a high level of expression of cyclooxygenase 2, but a subset of cases do not express without unknown reason. Aberrant methylation of CpG island of COX-2 was examined by using a series of gastric cancer cell lines and primary gastric cancers. Two out of 8 cell lines (25%) and 11 out of 93 (12%) primary cancers showed aberrant methylation of the 5' region of COX-2. Methylation of COX-2 was closely associated with loss of expression and treatment of methylation inhibitor, 5-deoxy-2'-azacytidine restored the expression of COX-2. A combined treatment of 5-deoxy-2'-azacytidine and a histone deacetylese inhibitor, trichostatin A, restored re-expression of the gene synergistically and chromatin immunoprecipitation analysis revealed that histone of methylated COX-2 promoter is deacetylated, indicating the role of cytosine methylation and histone deacetylation in the silencing of the gene. These results indicate that a subset of gastric cancer with COX-2 methylation evolves through the pathway that is independent of COX-2 expression and that COX-2 inhibitor may not be useful to induce apoptosis in these cases.
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PMID:Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer. 1177 76

The prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with a reduced risk of gastric cancer. The best-known target of these drugs is cyclooxygenase (COX); the COX-2 isoform is frequently up-regulated in gastric adenocarcinomas. Using the post-gastrectomy stomach as a model, the expression of COX-2 mRNA and protein has been investigated during tumour progression in the human stomach. COX-2 expression was comparable in gastric stump carcinomas and conventional gastric carcinomas and localized primarily to the cytoplasm of the neoplastic cells. COX-2 mRNA was elevated in biopsies containing intestinal metaplasia, as determined by reverse transcriptase polymerase chain reaction (RT-PCR). COX-2 immunopositivity became more frequent during progression from reactive epithelium to high-grade dysplasia, both in the epithelial and in the stromal cell compartment. Co-localization of COX-2-positive stromal cells was seen with CD68, alpha-smooth muscle actin (alpha-SMA), vimentin, and HLA-DR, but an as yet unidentified subpopulation of stromal cells remained. Co-localization with the macrophage marker CD68 was only observed in a minority of COX-2-positive cells. These data show that COX-2 expression is a relatively early event during carcinogenesis in the stomach. COX-2 expression increases during tumour progression in the stomach, suggesting a role for COX-2 expression in gastric tumourigenesis.
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PMID:Cyclooxygenase-2 expression during carcinogenesis in the human stomach. 1179 68


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