埃罗替尼和塞来昔布抑制胆管癌生长和血管生成

目的:观察表皮生长因子受体(EGFR)酪氨酸激酶抑制剂埃罗替尼与环氧合酶(COX-2)抑制剂塞来昔布对胆管癌荷瘤裸鼠的肿瘤生长协同抑制作用。方法:联合EGFR酪氨酸激酶抑制剂(EGFR-selective tyrosine kinaseinhibitor,EGFR TKI)埃罗替尼和COX-2抑制剂塞来昔布作用于胆管癌细胞株QBC939荷瘤裸鼠,评价药物体内作用效果。结果:埃罗替尼、塞来昔布联合用药显著抑制肿瘤生长,与对照组、埃罗替尼、塞来昔布单药组相比,均有显著性差异。抑制肿瘤生长的作用伴随EGFR下游活性蛋白p-MAPK的下调和VEGF、Ki-67表达的降低。肿瘤组织微血管密度降低。结论:埃罗替尼、塞来昔布抑制胆管癌荷瘤生长,抑制肿瘤细胞增殖,同时抑制肿瘤新生血管。两者具协同作用。靶向抑制EGFR和COX-2通路可以作为胆管癌的潜在治疗方法。     

COX-2在胆管癌中的表达及其与血管生成的关系

目的探讨环氧合酶-2(cyclooxygenase-2,COX-2)表达与胆管癌发生、发展、预后及其血管发生的关系。方法应用免疫组化技术检测COX-2、血管内皮生长因子(vascular endothelial growth factor,VEGF)、微血管密度(Microvessel density,MVD)在32例胆管癌组织标本和9例正常胆管组织标本中的表达。结果①胆管癌组织MVD值、COX-2、VEGF阳性表达率显著高于正常胆管组织;②胆管癌组织MVD值、VEGF的表达强度与胆管癌转移有显著相关性;③COX-2基因的表达与患者的性别、年龄、肿瘤的大小、分化及是否转移无关,但是与VEGF表达、MVD值成正相关。结论COX-2在胆管癌中高度表达可能与胆管癌的发生、发展、预后有关,并与胆管癌血管发生有密切联系。     

环氧化酶-2在前列腺肿瘤中的研究进展

环氧化酶-2(Cyclooxygenase-2，COX-2)是诱导型前列腺素内过氧化物合成酶。研究显示COX-2过度表达与某些上皮性肿瘤的发生发展关系密切。本文就COX-2结构特征、生物学特性、在前列腺肿瘤中的研究进展及COX-2抑制剂在预防治疗中的应用前景进行阐述。     

环氧化酶-2及其抑制剂在骨肉瘤中的作用

环氧化酶(COX)是合成前列腺素(PG)的限速酶.COX-2通过多种机制参与肿瘤发生和发展.研究发现,COX-2在骨肉瘤组织和细胞中高表达并有预后意义;可促进骨肉瘤细胞增殖并抑制其凋亡,促进肿瘤细胞侵袭、转移和肿瘤组织新生血管生成.选择性COX-2抑制剂可通过COX-2依赖性途径特异性地抑制PGE2合成而发挥抗肿瘤作用,还可通过多种非COX-2依赖性途径抑制肿瘤细胞增殖、侵袭和瘤组织血管生成.选择性COX-2抑制剂有望成为骨肉瘤辅助治疗的一种新途径.     

环氧化酶-2——骨肉瘤治疗靶点

环氧化酶(COX)是催化花生四烯酸合成前列腺素的限速酶.COX-2作为一种诱导性即刻反应基因,在炎症和肿瘤中高表达,骨肉瘤中亦发现COX-2高表达.COX-2的高表达与肿瘤的血管形成增加、细胞凋亡减少、侵袭性增加和免疫抑制相关.COX-2抑制剂则能通过COX-2途径和非COX-2途径(天冬氨酸特异性半胱氨酸蛋白酶、凋亡抑制基因bcl-2、过氧化物酶体增殖因子激活受体、神经酰胺、其他凋亡相关因子生存素、p53等)诱导肿瘤细胞凋亡,发挥抗肿瘤作用,因此COX-2成为骨肉瘤预防和治疗的靶点.COX-2抑制剂还能促进化疗和放疗效果,从而为骨肉瘤新辅助化疗和放疗等综合治疗提供理论依据.     

环氧合酶-2及其抑制剂与结直肠肿瘤

既往的实验研究和临床资料证明环氧合酶-2(COX-2)在肿瘤尤其是结直肠肿瘤细胞中高度表达，而COX-2抑制剂可以早期阻止结直肠癌的发生，同时对结直肠肿瘤也有治疗作用。     

胆管癌组织中信号转导及转录激活因子3信号通路相关基因的表达与意义

目的 探讨胆管癌组织中信号转导及转录激活因子3（STAT3）信号通路相关基因Survivin及环氧化酶2（COX-2）的表达及其与胆管癌患者临床病理特征和预后的关系.方法 收集2007年9月至2012年7月安徽医科大学附属省立医院收治的43例胆管癌患者的癌组织标本,收集同期行胆肠内引流术和胆管修复的12例肝内外胆管结石和胆管损伤患者的正常胆管组织标本作为对照.应用免疫组织化学染色检测胆管癌及正常胆管组织中STAT3、磷酸化STAT3（p-STAT3）、Survivin及COX-2蛋白的表达,并分析其与胆管癌患者临床病理特征和预后的关系.采用门诊或电话方式对胆管癌患者进行随访,随访时间截至2014年3月.计数资料采用x2检验,相关性分析采用Spearman检验.采用Kaplan-Meier法绘制生存曲线,生存分析采用Log-rank检验.结果 STAT3、p-STAT3、Survivin、COX-2蛋白在胆管癌组织中阳性表达率分别为69.8％ （30/43）、65.1％（28/43）、72.1％ （31/43）、79.1％（34/43）,在正常胆管组织中阳性表达率分别为41.7％（5/12）、8.3％（1/12）、16.7％（2/12）、41.7％（5/12）.p-STAT3、Survivin、COX-2蛋白在胆管癌组织中的阳性表达率显著高于正常胆管组织,两组比较,差异有统计学意义（x2=12.136,9.811,4.679,P＜0.05）.p-STAT3、Survivin、COX-2蛋白在胆管癌组织中的高表达与肿瘤局部浸润转移有关（x2=14.700,5.959,4.075,P＜0.05）;p-STAT3蛋白阳性表达与肿瘤神经侵犯有关（x2=10.384,P＜0.05）;Survivin、COX-2蛋白表达与胆管癌患者肿瘤神经侵犯无关（x2=2.718,3.024,P＞0.05）;p-STAT3、Survivin、COX-2蛋白表达与胆管癌患者性别、年龄、肿瘤位置、分化程度、肿瘤直径无关（x2=0.148,0.720,1.835,1.040,0.236;0.001,0.009,0.029,1.863,0.197;0.433,0.686,0.002,2.974,0.029,P＞0.05）.Survivin及COX-2蛋白的表达与p-STAT3呈正相关（r=0.524,0.583,P＜0.05）.43例胆管癌患者获得随访,随访时间为6个     

环氧化酶-2在膀胱移行细胞癌的临床研究进展

环氧化酶(COX)是前列腺素合成过程中的重要限速酶,目前至少已发现有两种同工酶:COX-1和COX-2。近年来的研究发现COX-2在多种癌症中高度表达,本文综述了COX-2在膀胱移行细胞癌的分级、分期、肿瘤预后以及其抑制剂应用前景等方面研究的最新进展。     

环氧合酶-2抑制剂NS-398对胃肠道间质瘤细胞株增殖的影响

胃肠道间质瘤(GIST)新的诊断定义是:一组独立起源于胃肠道间质干细胞的肿瘤~([1]).有研究结果显示环氧合酶-2(COX-2)在80%的GIST中持续表达,并且在恶性GIST和胃的GIST中表达更强,可能在GIST的增殖和进展中起作用,并且提出COX-2抑制剂可能作为基本的或辅助的治疗来预防GIST的复发~([2]).本研究旨在从细胞水平探讨特异COX-2抑制剂(NS-398)对人胃肠道间质瘤细胞株增殖的影响.     

尼美舒利对体外培养人胆管癌细胞QBC939增殖的抑制作用

近年来研究表明,环氧合酶-2（cyclooxygenase-2,COX-2）抑制剂具有抑制结肠癌、胃癌、肝癌等癌细胞增殖的作用.我们采用选择性COX-2抑制剂尼美舒利作用于胆管癌QBC939细胞,观察尼美舒利对胆管癌细胞的影响.……     

Cyclooxygenase-2 promotes prostate cancer progression

BACKGROUND: Cyclooxygenase (COX) -2, an inducible isoform of COX, has been observed to be expressed in prostate cancer. Several studies have reported that COX-2 overexpression is associated with carcinogenesis, cell growth, angiogenesis, apoptosis, and invasiveness in a variety of tumor types. METHODS: To investigate the function of COX-2 in prostate cancer directly, we stably transfected human full-length COX-2 cDNA into LNCaP cells (LNCaP-COX-2), which express low levels of endogenous COX-2. RESULTS: The level of COX-2 mRNA and protein and the COX activity in COX-2 LNCaP-COX-2 cells was significantly increased compared with parent and control-transfected cells. Overexpression of COX-2 increased both proliferation in vitro and tumor growth rate in vivo. However, the pro-tumor effect was neither associated with changes of androgen receptor (AR) expression level nor AR activity. Furthermore, addition of the major metabolites of COX-2-mediated arachidonic acid metabolism did not alter the proliferation of LNCaP-COX-2 cells in vitro. LNCaP-COX-2 cells had increased secretion of vascular endothelial growth factor (VEGF) protein, suggesting that angiogenesis induced by COX-2 stimulates tumor growth in vivo. CONCLUSION: These data demonstrate that COX-2 contributes to prostate cancer progression and suggest that it mediates this effect, in part, through increased VEGF.     

Cyclooxygenases

TWO ISOFORMS: There are two isoforms of cyclooxygenase (COX) with similar structure and metabolic activity. COX-1 is a constitutional enzyme. COX-2 is an inductible form. CYCLOOXYGENASE-1: COX-1 is present in most tissues, particularly in the kidney, the digestive tract mucosa, platelets, brain, liver and spleen. CYCLOOXYGENASE-2: COX-2 expression can be induced by an inflammatory process. Implicated in the development of certain cancers, COX-2 is expressed in numerous tumor cell lines and in most epithelial carcinomas. COX-2 favors tumor invasion and inhibits apoptosis. When it is absent, tumor growth is slower or stopped.     

The expression of cyclooxygenase in transitional cell carcinoma cell lines: its correlation with tumor differentiation, invasiveness and prostanoids production

OBJECTIVE: To evaluate the isozyme activities of COX-1 and COX-2 in TCC cells and correlate with cellular differentiation and tumor behavior.MATERIAL AND METHODS: Various TCC cell lines were characterized through several aspects: (1). to measure the content and the mRNA amount of COX-1 and COX-2, (2). to characterize the proteins of COX-1 and COX-2 by Western immunoblotting, (3). to measure the production of prostaglandin E2 and thromboxane B2 in culture media, and (4). to correlate these parameters with tumor differentiation and invasiveness.RESULTS: Seven out of 10 cell lines (70%) had significantly higher COX expression than normal urothelium. Tumors with lower-grade differentiation and less invasiveness had significantly higher content of COX-1 and COX-2 than those tumors with higher-grade differentiation and more invasive behavior (p<0.01). The expression of COX mRNA in TSGH8301, TCC8702 and RT4 were much higher than J82 which has minimal expression of COXs. Similarly, the COX-2 protein was much higher in TSGH8301, TCC8702 and RT4 when compared with J82. TSGH8301, TCC8702, and RT4 had high production of PGE2 and thromboxane B2 in their culture media. Increased secretions of PGE2 and thromboxane B2 were also observed in TCC8701, TCC9101, HT1376, and T24. The production of prostanoids is closely related to cytoplasmic COX expression of tumor cells.CONCLUSIONS: The expression of COX-1 and COX-2 is a common phenomenon in TCC cells and closely related to cellular differentiation and tumor invasiveness. The COX-2 inhibitors may play an important role in the control of TCC growth.     

Arachidonic acid and prostaglandins, inflammation and oncology

CYCLOOXYGENASE PATHWAY: Among the 3 metabolic pathways leading to oxidation of arachidonic acid, the cyclooxygenase (COX) pathway produces prostaglandin G2 that is rapidly transformed into prostaglandin H2. PROSTAGLANDINS: Prostaglandins are inflammation mediators that are strongly implicated in tumorgenesis. They participate in tumor initiation, promotion and growth. INFLAMMATION AND EPITHELIAL CANCER: Chronic inflammation is a risk factor for epithelial cancer. It induces prostaglandin synthesis via activation of COX-2. There is a cause and effect relationship between chronic inflammation and carcinogeneis via COX-2 expression. It has been demonstrated that COX-2 favors tumor invasion and inhibits apoptosis. Tumor growth is favored by PGE2-induced reduction in immunity; COX-2 inhibitors reinforce the immune response. Finally COX-2 is expressed in tumor neovessels and plays a role in angiogenesis.     

Subtotal nephrectomy stimulates cyclooxygenase 2 expression and prostacyclin synthesis in the rat remnant kidney

BACKGROUND: Recently, two isoforms of cyclooxygenase (COX) have been identified, a constitutive form (COX-1) and a mitogen-inducible form (COX-2). Several studies have suggested that COX is activated in renal insufficiency, but little is known about the relationship between progression of renal insufficiency and the COX isoforms. METHODS: Five-sixths-nephrectomized (NX) rats were used. 4, 8, and 12 weeks after nephrectomy, the renal cortical prostaglandin contents and the expression levels of the two isoforms of COX were determined by enzyme immunoassay and Western-blotting, respectively. The localization of COX was examined by immunohistochemistry. RESULTS: Renal cortical prostacyclin (PGI2) and COX-2 were significantly upregulated 8 and 12 weeks after NX, while COX-1 remained at the basal level. There was a high correlation between COX-2 and creatinine clearance (r = -0.845). There was also a high correlation between COX-2 and PGI2 (r = 0.816). Immunohistochemistry revealed the expression of COX-2 to be enhanced in the macula densa in NX rats. CONCLUSIONS: Renal cortical COX-2 and prostacyclin were upregulated corresponding to the progression of renal insufficiency in NX rats. These results suggest enhancement of COX-2 expression in the macula densa, perhaps stimulated by a decrease in renal blood flow which upregulates PGI2 synthesis to protect the kidney from ischemia in renal insufficiency.     

Altered monocyte cyclooxygenase response to lipopolysaccharide in type 1 diabetes

Type 1 diabetes is caused by adaptive immune responses, but innate immunity is important because monocytes infiltrate islets. Activated monocytes express cyclooxygenase (COX)-2, promoting prostaglandin-E(2) (PGE(2)) secretion, whereas COX-1 expression is constitutive. We aimed to define monocyte COX expression in type 1 diabetes basally and after lipopolysaccharide (LPS) stimulation. Isolated CD14(+) monocytes were analyzed for COX mRNA and protein expression from identical twins (discordant for type 1 diabetes) and control subjects. Basal monocyte COX mRNA, protein expression, and PGE(2) secretion were normal in type 1 diabetic subjects. After LPS, twins and control subjects showed a COX mRNA isoform switch with decreased COX-1 mRNA (P < 0.01), increased COX-2 mRNA (P < 0.01), and increased COX-2 protein expression (P < 0.01). Compared with control subjects, both diabetic and nondiabetic twins showed greater LPS-induced downregulation of monocyte COX-1 mRNA (P = 0.02), reduced upregulation of COX-2 mRNA and protein (P < 0.03), and greater inhibition by the COX-2 inhibitor di-isopropylfluorophosphate (DFP) of monocyte PGE(2) (P < 0.007). We demonstrate an alteration in monocyte COX mRNA expression as well as monocyte COX-2 and PGE(2) production after LPS in type 1 diabetic patients and their nondiabetic twins. Because COX-2 response to LPS is proinflammatory, an inherited reduced response would predispose to chronic inflammatory diseases such as type 1 diabetes.     

Cyclooxygenase inhibition as a strategy to ameliorate brain injury

Cyclooxygenase (COX) is the obligate, rate-limiting enzyme for the conversion of arachidonic acid into prostaglandins. Two COX enzymes have been identified: a constitutively expressed COX-1 and an inducible, highly regulated COX-2. Widely used to treat chronic inflammatory disorders, COX inhibitors have shown promise in attenuating inflammation associated with brain injury. However, the use of COX inhibition in the treatment of brain injury has met with mixed success. This review summarizes our current understanding of COX expression in the central nervous system and the effects of COX inhibitors on brain injury. Three major targets for COX inhibition in the treatment brain injury have been identified. These are the cerebrovasculature, COX-2 expression by vulnerable neurons, and the neuroinflammatory response. Evidence suggests that given the right treatment paradigm, COX inhibition can influence each of these three targets. Drug interactions and general considerations for administrative paradigms are also discussed. Although therapies targeted to specific prostaglandin species, such as PGE2, might prove more ameliorative for brain injury, at the present time non-specific COX inhibitors and COX-2 specific inhibitors are readily available to researchers and clinicians. We believe that COX inhibition will be a useful, ameliorative adjunct in the treatment of most forms of brain injury.     

Effects of selective cyclooxygenase inhibitors on ischemia/reperfusion-induced hepatic microcirculatory dysfunction in mice

We examined the effects of selective cyclooxygenase (COX) inhibition on hepatic warm ischemia/reperfusion (I/R) injury in mice. A selective COX-1 inhibitor, SC-560, selective COX-2 inhibitors, NS-398 and celecoxib, and indomethacin were administered 30 min before ischemia. Four hours after reperfusion, an in vivo microscopic study showed that I/R caused significant accumulation of leukocytes adhering to the hepatic microvessels and nonperfused sinusoids. Levels of plasma alanine transaminase (ALT) and tumor necrosis factor (TNF)-alpha also showed increases. SC-560, NS-398, celecoxib and indomethacin significantly reduced hepatic responses to I/R including microcirculatory dysfunction and release of ALT and TNF-alpha. Moreover, the effects of the thromboxane (TX) A(2) (TXA(2)) synthase inhibitor OKY-046 and the TXA(2) receptor antagonist S-1452 on hepatic responses to I/R exhibited results similar to those obtained with COX inhibitors. These results suggest that COX-1 and COX-2 contribute to I/R-induced hepatic microvascular and hepatocellular injury partly through TNF-alpha production, and that TXs derived from COX are partly responsible for I/R-induced liver injury.     

Effect of celecoxib and novel agent LC-1 in a hamster model of lung cancer

BACKGROUND: Lung cancer is the leading cause of cancer deaths in the United States. Inflammatory molecules, cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kappaB) have been implicated in lung carcinogenesis. The therapeutic potential of celecoxib, a COX-2 selective inhibitor, and LC-1, a pro-apoptotic drug with accompanying inhibition of NF-kappaB, were investigated. MATERIALS AND METHODS: Syrian golden hamsters (n = 140) underwent N-nitroso-bis(2-oxopropyl)amine (BOP) injection weekly for 6 wk. Hamsters were randomized into seven groups: placebo and low/high doses of LC-1, celecoxib, and LC-1/celecoxib. Treatments were given via orogastric lavage for 32 wk. Immunohistochemistry was used to determine COX-2 expression and NF-kappaB activity. Ki-67 labeling was used as an index of proliferation. COX activity was measured by prostaglandin E(2) enzyme-linked immunosorbent assay. RESULTS: BOP successfully induced lung adenocarcinoma in 63% of placebo animals. Lung tumors strongly expressed COX-2 and NF-kappaB. Prostaglandin E(2) levels were decreased in celecoxib compared with placebo groups (P < 0.05) reflecting suppression of COX activity, but no decrease in NF-kappaB was seen as measured by immunohistochemistry in the tumors. There was no significant difference in tumor size, tumor incidence, or tumor proliferation index between placebo and treatment groups. CONCLUSIONS: Carcinogen exposure results in increased COX-2 and NF-kappaB expression and suggests a role in carcinogenesis. Celecoxib and LC-1 did not have any effect in preventing lung cancer development when co-administered with and continued after the carcinogen BOP. Higher doses that can result in suppression of NF-kappaB activity will need to be explored to determine the viability of this approach to prevent lung cancer development.