胸腺瘤组织COX-2和EGFR表达及其临床意义的研究

目的:探讨环氧化酶-2(COX-2)、表皮生长因子受体(EGFR)在胸腺瘤组织中表达的生物学意义及其相互关系.方法:采用免疫组织化学SP法,检测53例胸腺瘤患者中COX-2、EGFR的表达,用5例正常胸腺组织作对照.结果:53例胸腺瘤组织中.随着Masaoka分期进展,COX-2、EGFR阳性表达率逐渐升高,差异有统计学意义,X2值分别为7.283和5.330,P值分别为0.007和0.021.COX-2和EGFR的阳性表达率与胸腺瘤的Masaoka分期及淋巴结转移等参数有关,P＜0.05;与胸腺瘤组织学分型无关,P＞0.05.COX-2与EGFR的表达呈正相关,r=0.811,P＜0.01.结论:胸腺瘤的浸润性发展与COX-2及EGFR的增强表达具有相关性,COX-2及EGFR在肿瘤细胞的增强表达可作为胸腺瘤恶性度和判断预后的重要生物学指标,并可为临床医生提供诊断和辅助治疗依据.     

幽门螺杆菌感染与胃癌组织环氧合酶2表皮生长因子受体和血管内皮生长因子的表达

目的 探讨环氧合酶2(COX-2)、表皮生长因子受体(EGFR)和血管内皮生长因子(VEGF)在胃癌组织中的表达,三者间的相关性及其与幽门螺杆菌(Hp)感染的关系.方法 采用免疫组化法检测61例胃癌组织及相应的20例癌旁组织中COX-2、EGFR和VEGF的表达;采用Westernblot方法检测10例胃癌组织及其相应癌旁组织中COX-2、EGFR和VEGF蛋白的表达;用快速尿素酶诊断法和13C呼气试验检测47例胃癌患者Hp感染状况.结果 免疫组化检测结果显示,COX-2、EGFR和VEGF在胃癌组织中的阳性表达率分别为59.02%、36.07%、60.66%,均明显高于癌旁组织(分别为25.00%、0和30.00%;均P＜0.05),三者在胃癌组织中的表达且呈正相关.COX-2和EGFR在Hp感染阳性胃癌组织中的阳性表达率分别为75.76%和45.45%,高于Hp感染阴性者(28.57%和14.29%;均P＜0.05).Western blot检测结果表明,胃癌组织中COX-2、EGFR和VEGF的灰度值分别为51.29±23.42、35.89±12.50和48.55±10.33,均显著高于癌旁组织(均P＜0.05).结论 COX-2、EGFR和VEGF在胃癌组织中高表达,Hp感染可能上调胃癌组织中COX-2、EGFR的表达.     

COX-2、VEGF和EGFR在胃癌中的表达和意义

目的:探讨COX-2、VEGF和EGFR这三种与肿瘤血管生成相关的蛋白在胃癌中的表达及其与临床病理特征的关系.方法:选取140例胃癌标本,应用免疫组化S-P法检测COX-2、VEGF和EGFR的表达, 并与临床参数进行比较分析.结果:COX-2、VEGF和EGFR在胃癌标本中的阳性表达率分别为49.29%(69/140)、47.86%(67/140)、45.71%(64/140).三者表达与年龄、性别、部位、肿瘤大小、分化程度均无关.胃癌中COX-2和EGFR的表达与浸润深度、淋巴结转移、TNM 分期显著相关(P<0.05) .VEGF表达与各种临床病理特征均无关(P>0.05).VEGF与COX-2表达呈正相关(P<0.000).结论:COX-2、EGFR与胃癌的浸润、转移及预后密切相关,可作为判断胃癌生物学行为和预后的重要参考指标.     

应用组织芯片法检测EGFR、COX-2在肺癌中的表达及生物学意义

背景与目的研究表明表皮生长因子受体(epidermal growth factor receptor,EGFR)和环氧合酶-2(cy-clooxygenase-2,COX-2)在多种实体瘤中存在高表达,并且可以通过相应的信号通路调节肿瘤的生长、侵袭和转移。本研究旨在探讨EGFR和COX-2在人类肺癌组织中表达的生物学意义及相互之间的关系。方法应用组织芯片技术结合免疫组织化学SP法检测89例原发肺癌、12例淋巴结转移性肺癌、12例癌前病变(不典型腺瘤样增生)和10例正常肺组织中EGFR、COX-2蛋白的表达情况。结果EGFR在肺癌组、癌前病变组、淋巴结转移性肺癌组中的阳性表达率分别为59.6%(53/89)、41.7%(5/12)和66.7%(8/12),COX-2在上述三组中的阳性表达率分别为52.8%(47/89)、41.7%(5/12)和66.7%(8/12),均较正常组明显升高(P<0.05)。EGFR和COX-2的表达与肺癌的组织学类型、临床分期和淋巴结转移有关(P<0.05),而与组织学分级、性别、年龄无关(P>0.05)。COX-2的表达还与肺癌的大体类型有关(P<0.05)。EGFR和COX-2...     

肺腺癌组织EGFR突变与p53和COX-2表达相关性及其临床意义

目的 针对表皮生长因子受体(epidermal growth factor receptor,EGFR)敏感突变的酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)治疗已成为肺癌精准治疗的典范,但多数患者在EGFR-TKI治疗有效后的8～16个月不可避免会出现获得性耐药.本研究探讨p53和COX-2在EGFR突变型晚期肺腺癌组织中的表达及其与患者临床特征的关系,并观察其表达对EGFR-TKI疗效的影响.方法 选取2014-03-01-2016-01-31于郑州大学第二附属医院病理确诊为EGFR突变型晚期肺腺癌并接受EGFR-TKI治疗的43例患者,利用免疫组织化学法检测p53和COX-2在EGFR突变型晚期肺腺癌组织中的表达;x2检验分析其与临床特征之间的相关性;生存分析采用Kaplan-Meier法;并进一步对影响患者无进展生存期(progression-free survival,PFS)的因素采用Cox比例风险回归模型分析.结果 43例EGFR突变型晚期肺腺癌患者中,p53、COX-2表达阳性率分别为41.8％和53.4％.p53表达随年龄增长(x2=3.939,P=0.047)及肿瘤分化程度减低(x2=4.182,P=0.041)而升高.COX-2表达与年龄、性别、吸烟史、肿瘤分化程度、临床分期及EGFR基因突变类型均未见明显相关性(P＞0.05).p53与COX-2表达无明显相关性,P＞0.05.患者接受EGFR-TKI治疗后,p53阴性组和阳性组中位PFS分别为12.0和7.5个月,差异有统计学意义,x2=4.726,P=0.030;COX-2阴性组和阳性组中位PFS分别为12.0和10.0个月,差异有统计学意义,x2=5.578,P=0.018.进一步行多因素Cox比例风险回归模型分析显示,p53 (HR=0.450,P=0.046)和COX-2(HR=0.424,P=0.021)表达均为EGFR突变型晚期肺腺癌患者PFS的独立影响因素.结论 EGFR突变型晚期肺腺癌组织中,p53和COX-2表达可能促进肿瘤进展,有望成为EGFR-TKI疗效的预测因子.     

COX-2在乳腺癌组织的表达及其与临床病理参数的相关性

目的:评价乳腺浸润性导管癌组织COX-2蛋白的表达情况及其与相关临床或病理参数间的相关性.方法:取101例资料完整的乳腺浸润性导管癌手术切除标本为研究对象,免疫组化方法检测COX-2、EGFR、cerbB-2等相关蛋白表达,采用χ2检验评估COX-2表达与不同的临床或病理参数间的关系.结果:肿瘤细胞中COX-2蛋白免疫组化阴性者15例(14.9%);阳性者86例(85.1%),COX-2高表达与乳腺癌脉管侵犯、淋巴结侵犯、分期、PR表达、cerbB-2表达及p53表达具有相关性.结论:乳腺浸润性导管癌中COX-2表达水平与肿瘤转移及分期均密切相关.     

siRNA靶向沉默COX-2对宫颈癌细胞VEGF、EGFR表达的影响

目的 探讨siRNA靶向沉默环氧合酶-2(COX-2)基因对宫颈癌HeLa细胞血管内皮生长因子(VEGF)和表皮生长因子受体(EGFR)表达的影响.方法 以人宫颈癌HeLa细胞为研究对象,采用COX-2 siRNA转染HeLa细胞作为转染组,以未转染的HeLa细胞作为空白对照组,以阴性对照siRNA转染HeLa细胞作为阴性对照组.逆转录聚合酶链反应(RT-PCR)检测COX-2、VEGF、EGFR基因的表达水平,蛋白质印迹法(Western blot)检测COX-2、VEGF、EGFR蛋白的表达水平,MTT法检测细胞的增殖情况,流式细胞仪检测细胞的凋亡情况,Tran-swell小室检测细胞的迁移和侵袭能力.结果 RT-PCR结果显示,转染组的COX-2、VEGF、EGFR基因表达水平均低于空白对照组和阴性对照组,差异均有统计学意义(P﹤0.05).Western blot结果显示,转染组的COX-2、VEGF、EGFR蛋白表达水平均低于空白对照组和阴性对照组,差异均有统计学意义(P﹤0.05).MTT检测结果显示,转染组的细胞增殖抑制率高于空白对照组和阴性对照组,差异均有统计学意义(P﹤0.05).流式细胞仪检测结果显示,转染组的细胞凋亡率高于空白对照组和阴性对照组,差异均有统计学意义(P﹤0.05).Transwell小室检测结果显示,转染组的细胞穿透率低于空白对照组和阴性对照组,差异均有统计学意义(P﹤0.05).结论siRNA靶向沉默COX-2基因能够抑制HeLa细胞中VEGF和EGFR的基因及蛋白表达水平,促进HeLa细胞凋亡,抑制HeLa细胞增殖,降低HeLa细胞的迁移及侵袭能力.     

光动力学疗法对小鼠Heps肝癌移植瘤COX-2表达的影响

目的 探讨光动力学疗法(photodynamic therapy,PDT)对Heps肝癌移植瘤环氧合酶-2(cyclooxygenase-2,COX-2)表达的影响及意义.方法 采用免疫组化染色,观察PDT后Heps肝癌移植瘤COX-2表达的动态变化.结果 PDT后2～72 h内4个时间点,肿瘤细胞COX-2表达较对照组明显升高(P<0.01),治疗后72 h肿瘤细胞COX-2表达较2、6和24 h下降(P<0.05).结论 PDT可诱导残存肿瘤细胞COX-2表达增加.     

环氧化酶-2抑制剂的抗肿瘤作用

环氧化酶(COX)有两种同功酶COX-1和COX-2.COX-2在正常组织中表达甚少,但在肿瘤和炎性细胞中表达较多.抑制COX-2可减少肿瘤细胞的分裂,增加其凋亡,并能抑制肿瘤细胞中血管的生成,体现出明显的抗肿瘤作用.流行病学、基础药理和临床等各方面的研究都显示非甾类抗炎药以及近期开发的特异性COX-2抑制剂具有预防和治疗肿瘤的作用.临床安全性较好,可望成为一类新型的抗肿瘤化学药物.     

EGFR的下调表达对鼻咽癌细胞粘附作用的实验研究

已有的研究表明:EGFR的过量表达增强了肿瘤的转移,但其确切的机理还知之甚少.同时,肿瘤细胞对胞外基质的粘附是肿瘤侵袭转移的重要步骤.为了探讨EGFR的表达改变是否影响肿瘤细胞对胞外基质的粘附作用,我们将构建的EGh反义序列表达质粒(pLXSN/AS)导入人过量表达EGFR的人类鼻咽癌细胞侏CNE-2Z中(pLXSN/AS)作对照转染).经G418筛选及125I-EGF结合分析,获得EGFR下调表达的CNE-2Z/AS克隆细胞,继而分别将CNE-2Z/AS,CNE-2Z及CNE-2Z/pLXSN细胞铺入含有层粘连蛋白(LN,10mg/ml)或纤粘连蛋白(FN,10mg/ml)的平皿中,于培养20min,40min,60min分别计数粘附于平的细胞数并绘制细胞生长曲线.结果表明:EGFR的下调表达能明显降低CNE-2Z细胞对FN,LN的粘附作用,而对照组细胞对FN,LN的粘附作用没有改变.这一结果提示:肿瘤细胞中EGFR的过量表达增强了肿瘤细胞对胞外基质的粘附作用,从而促进了肿瘤细胞分解基底膜和远端转移,这为进一步研究肿瘤转移机制奠     

Lipopolysaccharide initiates a bypass feedback loop of epidermal growth factor receptor signaling by HPS70-induced COX-2 in H22 hepatocarcinoma cells

LPS can induce TACE upregulation via signaling from TLR4-derived EGFR activation in tumor cells. The regulation and activity of TACE have been investigated with the observation that gene expression is upregulated in response to LPS followed by EGFR activation, however, the process remains poorly understood. In this study, we examined the effects of LPS on H22 hepatocarcinoma cells that displayed constitutively active TLR4 expression. Upon TLR4 shRNA transfection into H22 cells, HSP70 expression significantly increased. However, LPS induced early phosphorylation of EGFR in H22 cells, which reached maximum levels within 30?min. Inhibition of TLR4 in H22 cells resulted in a significant rise in both EGFR phosphorylation and TACE upregulation 24?h after exposure to LPS. Exogenous HSP70 also induced rapid phosphorylation of EGFR, upregulated the expression of COX-2 via a signaling pathway that involved TACE-dependent TGF-α release. Furthermore, inhibition of EGFR activation and reduction of COX-2 expression by COX-2 inhibitor prevented HSP70-induced cell invasion in vitro. These findings demonstrate that the biological importance of HSP70/COX-2 is crucial to the second, but not the first, phase of EGFR phosphorylation in tumor cells. The growth of tumor cells by inserting shRNA plasmid TLR4 combination with COX-2 inhibitor could be effectively reduced in LPS stimulation. We concluded that LPS triggered a bypass feedback loop of EGFR activation and involved HSP70/COX-2 in H22 cells by inhibition of TLR4 and that EGFR phosphorylation is implicated in tumor growth by LPS stimulation.     

Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect.

PURPOSE: Epidermal growth factor receptor (EGFR) and protein kinase A type I(PKAI) play an important role in the control of cancer cell growth and angiogenesis. Inhibitors of EGFR and PKAI have antitumor activity in vitro and in vivo in a variety of tumor types, and some of these agents are active after oral administration. Increasing evidence shows that cyclooxygenase (COX)-2 also plays a role in promoting cancer cell proliferation and angiogenesis. COX-2 expression can be induced by EGFR activation and is regulated by cAMP and PKA. Combination of an EGFR inhibitor with a nonselective COX-1/COX-2 inhibitor prevents the development of intestinal cancer in nude mice. Therefore, we investigated whether any cooperative antitumor effect can be obtained by the combined blockade of COX-2, EGFR, and PKAI. EXPERIMENTAL DESIGN: The COX-2 inhibitor SC-236 was combined with the selective EGFR tyrosine kinase inhibitor ZD1839 (Iressa) and the DNA/RNA-mixed backbone oligonucleotide AS-PKAI to study their effect on human cancer growth and angiogenesis, measuring vascular endothelial growth factor (VEGF) and basic fibroblast growth factor expression and vessel formation, in vitro and after oral administration of these agents in mice. RESULTS: A cooperative effect was observed with SC-236 in combination with either ZD1839 or AS-PKAI, as well as with all three agents together, on the proliferation of human colon and breast cancer cells in soft agar at doses that were ineffective for each agent alone. The antiproliferative effect was accompanied by inhibition of COX-2 expression. Moreover, combination of SC-236 with either agent or the triple combination markedly reduced VEGF secretion in the conditioned medium and completely suppressed VEGF and basic fibroblast growth factor expression. In nude mice bearing human colon cancer xenografts, a low, noninhibitory dose of SC-236 with ZD1839 and AS-PKAI, all given p.o., caused a dramatic cooperative antitumor effect, with no histological evidence of tumor in 60% of mice 5 weeks after treatment withdrawal, at which time all mice were alive. Moreover, analysis of tumor specimens revealed inhibition of vessel formation and expression of COX-2 and VEGF. CONCLUSIONS: This is the first demonstration that three novel agents blocking multiple signaling pathways, in absence of cytotoxic drugs, may have a potent antitumor and antiangiogenic activity after oral administration. Because all agents are under clinical evaluation, our results provide a rationale to translate this feasible therapeutic strategy into a clinical setting.     

Antitumor activity of ZD6474, a vascular endothelial growth factor-2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor, in combination with SC-236, a cyclooxygenase-2 inhibitor.

PURPOSE: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. Enhanced cyclooxygenase-2 (COX-2) expression has been linked to cancer cell proliferation, EGFR activation, VEGF secretion, and tumor-induced angiogenesis. ZD6474 is an orally available, small molecule, dual VEGF receptor-2 (VEGFR-2) and EGFR tyrosine kinase inhibitor. We investigated the activity of ZD6474 in combination with SC-236, a selective COX-2 inhibitor, to determine the antitumor activity of the simultaneous blockade of EGFR, COX-2, and VEGF functions. EXPERIMENTAL DESIGN: The antitumor activity in vitro and in vivo of ZD6474 and/or SC-236 was tested in human cancer cell lines with a functional EGFR autocrine pathway. RESULTS: The combination of ZD6474 and SC-236 determined supra-additive growth inhibition in all cancer cell lines tested. In nude mice bearing established human colon (GEO) or lung adenocarcinoma (A549) cancer xenografts and treated with ZD6474 and/or SC-236 for 3 weeks, a reversible tumor growth inhibition was seen with each agent, whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents. A long-term, 10-week treatment with ZD6474 plus SC-236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor-bearing mice and in 4 of 10 A549 tumor-bearing mice. CONCLUSIONS: This study provides a rationale for evaluating the simultaneous blockade of EGFR, COX-2, and VEGF signaling as cancer therapy in a clinical setting.     

The potential predictive value of cyclooxygenase-2 expression and increased risk of gastrointestinal hemorrhage in advanced non-small cell lung cancer patients treated with erlotinib and celecoxib.

PURPOSE: Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, potentiates antitumor effects of erlotinib in preclinical studies, and COX-2 is frequently expressed in non-small cell lung cancer (NSCLC). With these observations, we designed a phase II trial to evaluate the efficacy and safety of erlotinib plus celecoxib in advanced NSCLC. EXPERIMENTAL DESIGN: Previously treated stage IIIB/IV NSCLC patients were given celecoxib at 400 mg orally twice daily and erlotinib at 150 mg orally daily until disease progression. Planned accrual was 40 patients. Tissue was collected for epidermal growth factor receptor (EGFR) analysis and COX-2 immunohistochemistry. RESULTS: Twenty-six patients were enrolled (17 men, 9 women; median age, 66 years). Eighteen and 21 patients had tissue available for EGFR analysis and COX-2 immunohistochemistry, respectively. The median progression-free survival (PFS) and overall survival were 2.0 and 9.2 months, respectively. Eleven of 21 patients tested had increased tumor COX-2 expression, which was strongly associated with prolonged PFS (P=0.048). Four patients on anticoagulation or with a history of peptic ulcer disease had grade 3/grade 4 upper gastrointestinal bleeding (GIB), prompting early study closure. Three patients with GIB had endoscopy that found peptic ulcers. CONCLUSIONS: The combination of erlotinib and celecoxib does not seem superior to erlotinib alone in unselected patients. However, longer PFS with high-tumor COX-2 expression suggests that trials of EGFR and COX-2 inhibitors may be warranted in this patient subset. GIB observed in our trial supports excluding patients with a history of peptic ulcer disease or those requiring therapeutic anticoagulation from future EGFR and COX-2 inhibitor studies.     

Targeting cyclooxygenase-2 and the epidermal growth factor receptor for the prevention and treatment of intestinal cancer

Clinical and animal studies indicate a role for cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) in the development and progression of intestinal polyps and cancers. Although this combination of enzyme inhibition has shown synergy in intestinal polyp and tumor models, the exact mechanism for these effects remains undefined. Therefore, we sought to define the molecular mechanisms through which this process occurs. We observed a significant reduction in the number and size of small intestinal polyps in APC(min+/-) mice treated with either celecoxib (a selective COX-2 inhibitor) or erlotinib (Tarceva, an EGFR inhibitor). However, in combination, there was an overall prevention in the formation of polyps by over 96%. Furthermore, we observed a 70% reduction of colorectal xenograft tumors in mice treated with the combination and microarray analysis revealed genes involved in cell cycle progression were negatively regulated. Although we did not observe significant changes in mRNAs of genes with known apoptotic function, there was a significant increase of apoptosis in tumors from animals treated with the combination. The inhibition of EGFR also induced the down-regulation of COX-2 and further inhibited prostaglandin E2 formation. We observed similar effects on the prevention of intestinal adenomas and reduction of xenograft tumor volume when nonselective COX inhibitors were used in combination with erlotinib. Together, these findings suggest that the inhibition of both COX-2 and EGFR may provide a better therapeutic strategy than either single agent through a combination of decreased cellular proliferation and prostaglandin signaling as well as increased apoptosis.     

Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma

Cyclooxygenase-2 (COX-2), 5-Lipoxygenase (5-LOX), and epidermal growth factor receptor (EGRF) are over-expressed in human pancreatic ductal adenocarcinoma (PDAC). Using next-generation sequencing (NGS) analysis, we show significant increase in COX-2, 5-LOX, and EGFR expression during PDAC progression. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and EGFR simultaneously, we tested effects of licofelone (dual 5-LOX-COX inhibitor), and gefitinib (EGFR inhibitor), individually and in combination, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC using genetically engineered mice. Individually, licofelone (L) and gefitinib (G) significantly inhibited incidence of PDAC in male (72% L, 90% G, p < 0.0001) and female (90% L, 85% G, p < 0.0001) mice. The combination drug treatment produced complete inhibition of PDAC in both genders. Pancreata of mice receiving combination treatment showed significantly fewer Dclk1-positive cancer stem-like cells, inhibition of COX-2, 5-LOX, PCNA, EGFR and β-catenin expression (p < 0.05–0.0002), increased p21 expression. Significant changes in tumor immune responses and desmoplastic reaction was observed by NGS analysis in combination treatment (p < 0.05). In summary, early simultaneous targeting of 5-LOX-COX- and EGFR pathways may provide additive inhibitory effects leading to complete suppression of PDAC.     

COX-2/EGFR expression and survival among women with adenocarcinoma of the lung

Previous studies suggest that cyclooxygenase-2 (COX-2) expression may predict survival among patients with non-small cell lung cancer. COX-2 may interact with epidermal growth factor receptor (EGFR), suggesting that combined COX-2/EGFR expression may provide predictive value. The extent to which their independent or combined expression is associated with prognosis in women with adenocarcinoma of the lung is unknown. In the present study, we examined relationships between COX-2 expression (n = 238), EGFR expression (n = 158) and dual COX-2/EGFR expression (n = 157) and survival among women with adenocarcinoma of the lung. Overall survival was estimated by constructing Cox proportional hazards models adjusting for other significant variables and stratifying by stage at diagnosis and race. Clinical or demographic parameters were not associated with either COX-2 or EGFR expression. Patients with COX-2-positive tumors tended to have poorer prognosis than did patients with COX-2-negative tumors [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.01-2.78]. African-Americans with COX-2-positive tumors had a statistically non-significant higher risk of death than African-Americans with COX-2-negative tumors (HR 5.58, 95% CI 0.64-48.37). No association between COX-2 expression and survival was observed among Caucasians (HR 1.29, 95% CI 0.72-2.30). EGFR expression was associated with a 44% reduction in the risk of death (HR 0.56, 95% CI 0.32-0.98). COX-2-/EGFR+ tumor expression, but not COX-2+/EGFR+ tumor expression, was associated with survival when compared with other combined expression results. In conclusion, COX-2 and EGFR expression, but not combined COX-2+/EGFR+ expression, independently predict survival of women with adenocarcinoma of the lung.     

EGFR and COX-2 protein expression in non-small cell lung cancer and the correlation with clinical features

Background

To evaluate the expression of EGFR and COX-2 and their correlation with prognosis in NSCLC

Methods

The paraffin embedded tumor samples of 50 NSCLC patients receiving radical resection were analyzed immunohistochemically for EGFR and COX-2 expression and their prognostic values were explored.

Results

The positive rate of EGFR protein in NSCLC tumor cells was 46%, which was significantly higher than its expression in normal lung (p = 0.0234) and paracancerous tissues (p = 0.020). EGFR expression was significantly higher in nodal positive than in nodal negative patients (p = 0.04). The mean survival time for EGFR positive patients (31 months) was significantly lower than that for patients with EGFR negative expression (48 months) (p = 0.008,). In patients receiving post-operation thoracic irradiation, the mean survival time for EGFR positive patients was significantly lower than that for patients without EGFR positive expression (25 vs. 48 months, P = 0.004). The positive rate of COX-2 protein expression in NSCLC tumor cells was 90%, which was significantly higher than that in normal tissue(p = 0.00) and paracancerous tissue (p = 0.00). There was no correlation between COX-2 expression and patient survival, and no correlation between COX-2 and EGFR protein expression (P = 0.555).

Conclusions

COX-2 and EGFR are over-expressed in NSCLC. EGFR is an independent prognostic factor and a predictive factor for radiotherapy response in NSCLC.     

Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence.

PURPOSE: Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2-independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer. EXPERIMENTAL DESIGN: We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 weeks. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochemical and Western blot analysis were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E2 and tumor necrosis factor-alpha levels were determined using enzyme immunoassay/ELISA assays. RESULTS: The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E2, and tumor necrosis factor-alpha indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr(992) and Tyr(845)) and Akt (Ser(473)) was significant in rats given with these agents in combination. CONCLUSIONS: In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events.