COX-2抑制剂在胃癌中的研究进展

环氧合酶-2(COX-2)是催化花生四烯酸合成前列腺素的关键限速酶,呈诱导性表达在病变组织中,参与各种损伤性化学、肿瘤、炎症、发热、凝血、疼痛等病理过程。近年来大量研究表明,COX-2在胃癌的发生发展及转移中起着关键性作用,COX-2在肿瘤增殖、血管生成、侵袭转移及抑制细胞凋亡中的作用已经受到医学界的关注,诸多研究表明选择性COX-2抑制剂不仅能够抑制胃癌细胞的增殖和促进癌细胞凋亡,还能降低胃癌细胞的侵袭转移能力,有助于胃癌的防治。随着COX-2与胃癌关系研究的深入,作为胃癌防治靶点之一的COX-2,已经成为胃癌治疗的热点。本文主要讨论COX-2及其抑制剂在胃癌的中作用及研究进展。     

EGFR在胃癌中的研究进展

表皮生长因子受体（EGFR）通过下游的信号传导途径参与肿瘤细胞增殖、血管生成、侵袭、转移及凋亡抑制等的基因调控,在多种肿瘤组织中有高表达。近几年在胃癌的研究中显示：EGFR在胃癌中有高表达,与胃癌的发生、发展及生物学行为密切相关,被认为是胃癌等肿瘤治疗的理想靶点。当前以EGFR为靶点的生物治疗成为胃癌新的研究热点,本文就其近几年EGFR在胃癌的表达、预后及靶向治疗等研究现状作一综述。     

微小RNA与胃癌的关系

微小RNA（microRNA、miRNA）与胃癌的发生发展可通过调控其靶基因参与的信号传导通路,影响胃癌的发生、侵袭和转移等过程,发挥着类似于癌基因或抑癌基因的作用。目前,已发现多种microR—NA与胃癌关系密切,包括通过调节周期蛋白依赖性蛋白激酶（Cdk）表达影响胃癌细胞增殖的miR-106b-93～25家族、miR-222—221家族和抑制高迁移率族蛋白A2（HMGA2）基因表达抑制胃癌细胞转移的miR-129和let-一7miRNA家族等。另有研究表明,miR-d21和miR-31检测阳性率显著高于血清CEA,可能成为新的胃癌肿瘤标志物。miR-15b和miR-16与胃癌多药耐药的关系也说明microRNA可能成为胃癌治疗新的靶点。     

环氧合酶-2在肿瘤浸润和转移中的作用及治疗研究

环氧合酶-2(COX-2)是合成前列腺素的性,其高表达可促进肿瘤转移.COX-2通过改变细胞表面粘着因子和细胞外基质、促进肿瘤血管生成以及改变肿瘤微环境等一系列病理生理变化促进肿瘤转移.COX-2已成为预防和阻止肿瘤转移的药靶,COX-2抑制剂对肿瘤有一定疗效.现就近年来COx.2在肿瘤浸润和转移中的作用及治疗研究作一综述.     

环氧化酶-2与肺损伤

肺损伤是指各种致病因素（物理、化学和生物性因素）作用于肺脏组织而引起的肺组织细胞的变性、坏死及肺功能的改变,多种炎性介质及细胞因子参与了肺损伤的过程。环氧化酶-2（COX-2）为一种诱导酶,当细胞受到炎症等刺激时可高表达,是炎症介导的细胞毒性重要的决定因素之一。在各种原因所导致的肺损伤中,COX-2表达增多的现象提示COX-2在肺损伤发生发展中具有重要作用,COX-2作为肺损伤的治疗靶点将成为今后研究的热点。     

COX-2 与mPGES-1 在肾透明细胞癌中的表达及临床意义

目的:探讨环氧合酶-2(COX-2)和膜结合型前列腺素E2合成酶1(mPGES-1)在肾透明细胞癌组织中的表达及临床意义。方法:采用免疫组化SP法分别检测49例肾透明细胞癌组织标本和21例正常肾组织标本中COX-2和mPGES-1的表达。结果:COX-2在正常肾组织中的阳性表达率为4.8%,在肾透明细胞癌组织中的阳性表达率为53.1%(P<0.05);mPGES-1在正常肾组织中的阳性表达率为4.8%,在肾透明细胞癌组织中的阳性表达率为40.8%(P<0.05);COX-2和mPGES-1的高表达均与肾透明细胞癌的病理分级和临床分期无相关性(P>0.05);COX-2和mPGES-1在肾透明细胞癌中的表达呈正相关(P<0.05),r=0.5。结论:COX-2和mPGES-1在肾透明细胞癌发生及发展过程中共同发挥重要作用;COX-2和mPGES-1可能成为肾透明细胞癌新的治疗靶点。     

靶向mTOR的抗肿瘤与抗衰老药物研究进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种丝/苏氨酸蛋白激酶,在调节细胞生长、增殖、存活、血管生成、蛋白质合成、细胞周期中发挥着重要的作用。mTOR信号通路异常与肿瘤及衰老密切相关,已成为相关疾病治疗的靶点。该文综述了mTOR对肿瘤和衰老调控的研究进展,对于揭示肿瘤及衰老相关疾病的发生机制具有重要意义,并为研发以mTOR信号通路为靶点的抗肿瘤、抗衰老的治疗药物提供了新的思路和方法。     

环氧化酶-2与肺损伤

肺损伤是指各种致病因素(物理、化学和生物性因素)作用于肺脏组织而引起的肺组织细胞的变性、坏死及肺功能的改变,多种炎性介质及细胞因子参与了肺损伤的过程.环氧化酶-2(COx-2)为一种诱导酶,当细胞受到炎症等刺激时可高表达,是炎症介导的细胞毒性重要的决定因素之一.在各种原因所导致的肺损伤中,COX-2表达增多的现象提示COX-2在肺损伤发生发展中具有重要作用,COX-2作为肺损伤的治疗靶点将成为今后研究的热点.     

COX-2 与血液恶性疾病

环氧化酶(COX-2)是体内前列腺素(PG)合成过程中重要的限速酶,它在正常组织中表达甚少,但在肿瘤和炎性细胞中表达较多,近年来的研究表明COX-2的过表达与肿瘤的发生,发展有关,使COX-2成为肿瘤研究的新热点,但COX-2在实体肿瘤中的研究较多而与血液恶性疾病之间关系国内报道较少,现就COX-2的研究进展以及在血液恶性肿瘤中的作用做一综述。     

肿瘤微环境对胃癌化疗耐药的影响

胃癌是一种消化道高发恶性肿瘤，化疗耐药是其相关性死亡的主要原因之一。肿瘤微环境(tumor microenvironment,TME)通过各种途径与机制促进胃癌化疗耐药，因而TME可能是评估肿瘤发展方向和克服治疗耐药的关键。鉴于治疗胃癌化疗耐药缺乏有效的临床方案，本文综述了TME中的细胞成分、非细胞成分与胃癌细胞化疗耐药之间的联系，以及TME中主要成分与化疗耐药相关联的生物标志物和治疗靶点。此外，本文进一步讨论了TME中不同细胞促进胃癌化疗抵抗的机制，总结了潜在的调节因子与药物，旨在为临床解决胃癌化疗耐药性提供新的角度，并为胃癌防治提供新思路。     

Role of cyclooxygenase-2 in tumor progression and immune regulation in lung cancer

Lung cancer is the leading cause of cancer death all over the world. The low 5-year survival rate (under 15%) has changed minimally in the last 25 years. Amongst different types of lung cancers, non-small cell lung carcinoma (NSCLC) types account 25-40%. To improve the survival of lung cancer patients, new therapeutic strategies are needed. The search for improved therapies has led to the investigation of agents that target novel pathways involved in tumor proliferation, invasion, survival and immune regulation. Cyclooxygenase-2 (COX-2) is one of the novel targets under evaluation for NSCLC therapy and chemoprevention. Although multiple genetic alterations are necessary for lung cancer invasion and metastasis, COX-2 may act as central element in orchestring these processes. COX-2 plays an important role in all aspects of tumor development and growth. It also plays a pivotal role in regulation of cytokines and immune responses in NSCLC patients. In this article, we review the experimental and clinical evidences on the possible link between COX and NSCLC.     

Potential misidentification of cyclooxygenase-2 by western blot analysis and prevention through the inclusion of appropriate controls

Cyclooxygenase (COX)-2 plays an important role in the development of cancer and has been recognized as a potential therapeutic target. Because nonsteroidal anti-inflammatory drugs (NSAIDs) are able to inhibit the activity of this enzyme, the potential efficacy of such drugs for purposes of cancer prevention or therapy is an area of intense research. Therefore, it is of critical importance to unequivocally determine the expression levels of COX-2 protein in tumor cells. In this regard, there are several conflicting reports in the literature where the same type of tumor cell lines were reported as COX-2 positive and as COX-2 negative. We found that during Western blot analysis of COX-2 positive and COX-2 negative cells, different antibodies to COX-2 protein are able to generate strong signals, which are false-positives and can be confused with COX-2. Thus, we believe that some of the conflicting reports on COX-2 expression in tumor cell lines could be the result of improper interpretation of the Western blot signals. Here, we present some of these pitfalls and suggest the inclusion of appropriate controls to unequivocally identify COX-2 protein levels.     

COX-2 inhibitor, NS398, enhances Fas-mediated apoptosis via modulation of the PTEN-Akt pathway in human gastric carcinoma cell lines

A variety of human cancer cells are resistant to Fas ligand and anti-Fas antibody induced apoptosis. Previously, we reported that human gastric carcinoma cell lines were resistant to the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. Cyclooxygenase (COX)-2 is known to be expressed in many human malignancies, and is correlated with tumor progression and resistance to apoptosis. This study examined whether NS398, a COX-2 inhibitor, inhibited cell proliferation and increased Fas-mediated apoptosis in human gastric carcinoma cell lines. Treatment of NS398 inhibited cell proliferation in MKN-45, which expressed the highest level of COX-2 among seven human gastric carcinoma cell lines, in a dose- and time-dependent manner, in contrast to less prominent effects in KATO-III, which expresses no COX-2. Although the treatment of CH-11 induced apoptosis in both cells, the simultaneous treatment of NS398 and CH-11 remarkably induced apoptosis, as confirmed by Hoechst 33258 staining and the terminal deoxynucleotidyl transferase- mediated dUTP-digoxigenin nick-end labeling (TUNEL) method in MKN-45. Flow cytometric analysis also revealed the increased pre-G1 fraction by the simultaneous treatment. The treatment of NS398 induced upregulation of Bad and PTEN, and downregulation of phosphorylated Akt (Thr308). These findings suggest that COX-2 might inhibit Fas-mediated apoptosis in human gastric carcinoma cell lines, especially MKN-45, by modulating PTEN and Akt.     

COX-2及其抑制剂在肿瘤防治中的作用

环氧化酶（cyclooxygenase,COX）是前列腺素合成途径中主要的限速酶之一,参与炎症、发热、出凝血等病理生理过程。COX-2在肿瘤发生发展、转移、凋亡抑制及促进肿瘤血管生成等方面发挥重要作用,己成为肿瘤防治的一个新靶点;COX-2及其抑制剂在肿瘤预防、放疗、化疗、生物疗法中具有广阔应用前景。本文就COX-2及其抑制剂在肿瘤防治中的进展作一详细综述。     

罗格列酮抑制人胃腺癌SGC7901增殖机制的研究

目的：探讨在体外不同浓度的过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮（ROZ）对人胃癌细胞系SGC7901的生长及细胞周期的影响。方法：采用MTT法比色实验、集落形成实验、电子显微镜,透射电镜,流式细胞仪分别观察不同浓度罗格列酮0.08μmol/L,0.4μmol/L,2μmol/L,10μmol/L,50μmol/L,作用于SGC7901细胞,对细胞增殖,细胞形态和细胞周期的影响。结果：ROZ可抑制SGC7901细胞的生长以及SGC7901细胞集落的形成,并呈现剂量依赖性,其半数抑制浓度（IC50）约为50μmol/L。透射电镜低倍镜以及高倍下可见凋亡细胞。流式细胞仪结果显示,ROZ可抑制SGC7901细胞,引起G0/G1期细胞大量增加,S期细胞减少,且细胞周期停滞于G1期。结论：ROZ具有抗肿瘤作用,能够抑制SGC7901细胞的增殖并诱导凋亡,这种作用与其诱导细胞周期G0/G1期的停滞和诱导凋亡作用有关。因此,ROZ有望成为胃癌治疗的辅助用药亦或治疗药,PPARγ有潜力成为肿瘤治疗的新靶点。     

喉癌相关基因的研究进展

喉癌是头颈部常见恶性肿瘤之一,以喉鳞状细胞癌为多。喉癌的发生和发展是一个多基因参与、多阶段、多层面的复杂过程。目前研究发现,喉癌与EGFR、COX-2、Survivin、VEGF、STAT3、p16、p53和Cyclin D1等基因相关。通过对这些基因的深入研究,基因治疗将为喉癌的临床治疗和预防提供新途径,对人类战胜喉癌有着极其重要的意义。     

In vitro antiproliferative activity against human colon cancer cell lines of representative 4-thiazolidinones. Part I

The characterization of two cyclooxygenase isoforms (COX), the rate-limiting enzyme for the synthesis of prostaglandins (PGs) from arachidonic acid, has allowed the development of COX-2 selective inhibitors as non-steroidal anti-inflammatory drugs (NSAIDs) with significant gastric tolerability. However, PGs are also important in cancer pathogenesis. Thus, there is an increasing interest in studying COX-2 inhibitors as potential drugs aimed at the prevention and treatment of cancer, especially colorectal cancer. The purpose of this study was to determine the inhibitory effects of some representative 4-thiazolidinones, already widely investigated as potential NSAIDs, on the growth of five human colon carcinoma cell lines with a different COX-2 expression, and to correlate them with COX-2 inhibitory properties. Our results preliminarily revealed that 2-phenylimino derivative 3 and 2,4-thiazolidindione 4 were the most active compounds. In particular, 3 mainly inhibited the HT29 cell line characterized by a high COX-2 expression, whereas 4 showed antiproliferative properties on all tested cell lines, suggesting molecular targets other than COX-2 inhibition.     

Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44

Elevated tumor cyclooxygenase (COX-2) expression is associated with increased angiogenesis, tumor invasion, and suppression of host immunity. We have previously shown that genetic inhibition of tumor COX-2 expression reverses the immunosuppression induced by non-small cell lung cancer (NSCLC). To assess the impact of COX-2 expression in lung cancer invasiveness, NSCLC cell lines were transduced with a retroviral vector expressing the human COX-2 cDNA in the sense (COX-2-S) and antisense (COX-2-AS) orientations. COX-2-S clones expressed significantly more COX-2 protein, produced 10-fold more prostaglandin E(2), and demonstrated an enhanced invasive capacity compared with control vector-transduced or parental cells. CD44, the cell surface receptor for hyaluronate, was overexpressed in COX-2-S cells, and specific blockade of CD44 significantly decreased tumor cell invasion. In contrast, COX-2-AS clones had a very limited capacity for invasion and showed diminished expression of CD44. These findings suggest that a COX-2-mediated, CD44-dependent pathway is operative in NSCLC invasion. Because tumor COX-2 expression appears to have a multifaceted role in conferring the malignant phenotype, COX-2 may be an important target for gene or pharmacologic therapy in NSCLC.     

胃癌的过继性免疫治疗研究进展

胃癌是目前世界上发病率及致死率较高的恶性肿瘤之一,在东亚地区尤其显著。针对胃癌的治疗手段仍是传统的手术联合化疗、放疗为主,尽管靶向药物治疗提供了新的选择,但其对晚期胃癌的疗效仍然有限。胃癌的免疫治疗作为独特的治疗手段,在近十多年发展较为活跃,特别是过继性免疫治疗手段不断有创新。过继性免疫治疗主要依赖回输具有抗肿瘤活性的细胞,目前回输的细胞由具有非特异性抗肿瘤作用向具有特异性抗肿瘤作用演变,特别是嵌合性抗原T细胞治疗的出现,为进展期胃癌患者提供了有一种潜在的选择。本文对胃癌过继性免疫治疗中采用的不同免疫活性细胞的作用机制、临床应用等进行总结,并针对其不足提出利用基因工程技术增强治疗靶向性、降低免疫逃逸的研究方向。