This article reviews the pathogenic mechanism of nonsteroidal anti-inflammatory drug(NSAID)-induced gastric damage,focusing on the relation between cyclooxygenase(COX) inhibition and various functional events.NSAIDs,s...This article reviews the pathogenic mechanism of nonsteroidal anti-inflammatory drug(NSAID)-induced gastric damage,focusing on the relation between cyclooxygenase(COX) inhibition and various functional events.NSAIDs,such as indomethacin,at a dose that inhibits prostaglandin(PG) production,enhance gastric motility,resulting in an increase in mucosal permeability,neutrophil infiltration and oxyradical production,and eventually producing gastric lesions.These lesions are prevented by pretreatment with PGE 2 and antisecretory drugs,and also via an atropine-sensitive mechanism,not related to antisecretory action.Although neither rofecoxib(a selective COX-2 inhibitor) nor SC-560(a selective COX-1 inhibitor) alone damages the stomach,the combined administration of these drugs provokes gastric lesions.SC-560,but not rofecoxib,decreases prostaglandin E 2(PGE 2) production and causes gastric hypermotility and an increase in mucosal permeability.COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib.The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility.In addition,selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions,including adrenalectomy,arthritis,and Helicobacter pylori-infection.In summary,gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage,and the response,causally related with PG deficiency due to COX-1 inhibition,occurs prior to other pathogenic events such as increased mucosal permeability;and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2,the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility,and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.展开更多
AIM:To study the relationship between the cyclooxy-genase(COX)-2 gene and the proliferation and apopto-sis of esophageal squamous carcinoma EC109 cells.METHODS:The techniques of RNA interference(RNAi)and cell transfec...AIM:To study the relationship between the cyclooxy-genase(COX)-2 gene and the proliferation and apopto-sis of esophageal squamous carcinoma EC109 cells.METHODS:The techniques of RNA interference(RNAi)and cell transfection,as well as the levels of oncogenic-ity in nude mice,were used to study the role of COX-2 in the esophageal squamous carcinoma cell(ESCC)line EC109.Following RNAi and transfection,Western blot-ting analysis was used to determine the expression of the COX-2 protein.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide(MTT)reduction assay was used to evaluate cell growth,and flow cytometry was used to detect cell apoptosis.RESULTS:Western blotting analysis demonstrated that COX-2 expression was significantly reduced in EC109 cells treated with COX-2-specif ic short interfering RNA(siRNA)but was increased in EC109 cells transfected with COX-2.Furthermore,COX-2 siRNA treatment in-hibited cell proliferation(P < 0.01)and induced apop-tosis in EC109 cells,as determined by an MTT assay and by flow cytometry,respectively.In contrast,trans-fected COX-2 led to increased cell proliferation(P < 0.05)and decreased apoptosis in EC109 cells.In addition,combination treatment of cells with COX-2 siRNA and aspirin had a synergistic effect(P < 0.01).For experi-ments measuring tumorigenicity,xenograft tumors of a greater volume and weight were found in the COX-2 group compared with other groups(P < 0.05).A large dose of aspirin inhibited tumor growth in nude mice ef-fectively(P < 0.05),and the rate of tumor suppression was 51.8% in the high-dose aspirin group.CONCLUSION:COX-2 plays a very critical role in ESCC carcinogenesis,and COX-2 siRNA combined with aspirin has the potential to be an anticancer therapy for the treatment of ESCC.展开更多
AIM:To correlate cyclooxygenase-2(COX-2)expression profile with clinical and pathological variables to assess their prognostic/predictive value in colorectal carcinoma(CRC).METHODS:Archival tumor samples were analyzed...AIM:To correlate cyclooxygenase-2(COX-2)expression profile with clinical and pathological variables to assess their prognostic/predictive value in colorectal carcinoma(CRC).METHODS:Archival tumor samples were analyzed using immunohistochemistry for COX-2 expression in 94 patients with CRC.Patients were diagnosed and treatedat the Departments of Surgery and Oncology,King Abdulaziz University Hospital,Saudi Arabia.RESULTS:Fifty-six percent of the tumors showed positive cytoplasmic COX-2 expression,whereas 44%of cases were completely COX-2-negative.There were no significant correlations between COX-2 expression and sex,age,grade or tumor location.However,COX-2 expression revealed a significant correlation with tumor stage(P=0.01)and distant metastasis(P=0.02),and a borderline association with lymph node involvement(P =0.07).Tumors with high COX-2 expression showed a higher recurrence rate than tumors with no expression(P<0.009).In univariate Kaplan-Meier survival analysis,there was a significant(P=0.026)difference in disease-free survival between COX-2-positive and negative tumors in favor of the latter.COX-2 expression did not significantly predict disease-specific survival,which was much shorter for COX-2-positive tumors.In multivariate(COX)models,COX-2 did not appear among the independent predictors of disease-free survival or disease-specific survival.CONCLUSION:COX-2 expression seems to provide useful prognostic information in CRC,while predicting the patients at high risk for recurrent disease.展开更多
文摘This article reviews the pathogenic mechanism of nonsteroidal anti-inflammatory drug(NSAID)-induced gastric damage,focusing on the relation between cyclooxygenase(COX) inhibition and various functional events.NSAIDs,such as indomethacin,at a dose that inhibits prostaglandin(PG) production,enhance gastric motility,resulting in an increase in mucosal permeability,neutrophil infiltration and oxyradical production,and eventually producing gastric lesions.These lesions are prevented by pretreatment with PGE 2 and antisecretory drugs,and also via an atropine-sensitive mechanism,not related to antisecretory action.Although neither rofecoxib(a selective COX-2 inhibitor) nor SC-560(a selective COX-1 inhibitor) alone damages the stomach,the combined administration of these drugs provokes gastric lesions.SC-560,but not rofecoxib,decreases prostaglandin E 2(PGE 2) production and causes gastric hypermotility and an increase in mucosal permeability.COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib.The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility.In addition,selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions,including adrenalectomy,arthritis,and Helicobacter pylori-infection.In summary,gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage,and the response,causally related with PG deficiency due to COX-1 inhibition,occurs prior to other pathogenic events such as increased mucosal permeability;and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2,the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility,and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.
基金Supported by The National Natural Science Foundation of China,No.81071974The National 863 High Technology Research and Development Plan of China,No.2007AA02Z4Z4
文摘AIM:To study the relationship between the cyclooxy-genase(COX)-2 gene and the proliferation and apopto-sis of esophageal squamous carcinoma EC109 cells.METHODS:The techniques of RNA interference(RNAi)and cell transfection,as well as the levels of oncogenic-ity in nude mice,were used to study the role of COX-2 in the esophageal squamous carcinoma cell(ESCC)line EC109.Following RNAi and transfection,Western blot-ting analysis was used to determine the expression of the COX-2 protein.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide(MTT)reduction assay was used to evaluate cell growth,and flow cytometry was used to detect cell apoptosis.RESULTS:Western blotting analysis demonstrated that COX-2 expression was significantly reduced in EC109 cells treated with COX-2-specif ic short interfering RNA(siRNA)but was increased in EC109 cells transfected with COX-2.Furthermore,COX-2 siRNA treatment in-hibited cell proliferation(P < 0.01)and induced apop-tosis in EC109 cells,as determined by an MTT assay and by flow cytometry,respectively.In contrast,trans-fected COX-2 led to increased cell proliferation(P < 0.05)and decreased apoptosis in EC109 cells.In addition,combination treatment of cells with COX-2 siRNA and aspirin had a synergistic effect(P < 0.01).For experi-ments measuring tumorigenicity,xenograft tumors of a greater volume and weight were found in the COX-2 group compared with other groups(P < 0.05).A large dose of aspirin inhibited tumor growth in nude mice ef-fectively(P < 0.05),and the rate of tumor suppression was 51.8% in the high-dose aspirin group.CONCLUSION:COX-2 plays a very critical role in ESCC carcinogenesis,and COX-2 siRNA combined with aspirin has the potential to be an anticancer therapy for the treatment of ESCC.
基金Supported by Scientific Chair for Colorectal Cancer,King Abdul-Aziz University,Jeddah,Saudi Arabia
文摘AIM:To correlate cyclooxygenase-2(COX-2)expression profile with clinical and pathological variables to assess their prognostic/predictive value in colorectal carcinoma(CRC).METHODS:Archival tumor samples were analyzed using immunohistochemistry for COX-2 expression in 94 patients with CRC.Patients were diagnosed and treatedat the Departments of Surgery and Oncology,King Abdulaziz University Hospital,Saudi Arabia.RESULTS:Fifty-six percent of the tumors showed positive cytoplasmic COX-2 expression,whereas 44%of cases were completely COX-2-negative.There were no significant correlations between COX-2 expression and sex,age,grade or tumor location.However,COX-2 expression revealed a significant correlation with tumor stage(P=0.01)and distant metastasis(P=0.02),and a borderline association with lymph node involvement(P =0.07).Tumors with high COX-2 expression showed a higher recurrence rate than tumors with no expression(P<0.009).In univariate Kaplan-Meier survival analysis,there was a significant(P=0.026)difference in disease-free survival between COX-2-positive and negative tumors in favor of the latter.COX-2 expression did not significantly predict disease-specific survival,which was much shorter for COX-2-positive tumors.In multivariate(COX)models,COX-2 did not appear among the independent predictors of disease-free survival or disease-specific survival.CONCLUSION:COX-2 expression seems to provide useful prognostic information in CRC,while predicting the patients at high risk for recurrent disease.
