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与骨肉瘤

环氧化酶-2(COX-2)及其抑制剂是近年肿瘤防治研究的热点之一.目前研究表明COX-2通过多种途径参与骨肉瘤的发生、发展和转移,并对病人的预后产生积极影响.选择性COX-2抑制剂能有效地抑制骨肉瘤细胞的增殖、浸润和转移,并能缓解骨肿瘤引起的疼痛、减轻骨破坏,给骨肉瘤治疗带来了新希望.     

人乳腺癌组织中环氧化酶-2基因的表达及其意义

研究结果显示，长期有规律服用非甾体抗炎药(NSAIDs)可以降低女性患乳腺癌的风险性。而此类药物是通过抑制环氧化酶(COX-2)发挥作用的。COX-2为诱导型环氧化酶，在正常情况下多数组织细胞不表达，然而COX-2基因在消化道肿瘤、前列腺癌、膀胱癌等多种癌组织中过表达。我们在基因和蛋白水平上检测人乳腺癌组织中的表达情况及其与乳腺癌临床病理特征的关系，旨在进一步探讨COX-2在乳腺癌发生发展中的意义。     

环氧化酶-2在尿路上皮癌的研究

尿路上皮癌是泌尿系统最常见的恶性肿瘤,其中膀胱发病率最高。近年来研究发现环氧化酶-2（COX-2）在肿瘤细胞凋亡、血管生成及免疫抑制中发挥重要的作用,能够促进肿瘤的发生、发展。COX-2在膀胱尿路上度癌的研究已有相关报道,COX-2作为膀胱肿瘤的治疗靶点正被广泛关注,但对于COX-2与上尿路上皮癌的关系的研究则很少。本文就COX-2在尿路上皮癌的研究作一综述。     

消化道肿瘤环氧合酶-2表达与凋亡抑制蛋白及化疗药敏性的关系

目的 探讨消化道肿瘤环氧合酶(COX)-2表达与凋亡抑制蛋白及体外化疗药敏性的关系.方法 对84例胃癌、大肠癌标本进行噻唑蓝(MTT)比色法体外化疗药物敏感性实验,并进行COX-2、p53、Survivin、bel-2免疫组织化学染色.结果 肿瘤组织COX-2、p53、Survivin、bel-2表达率分别为70.3%、64.3%、89.3%、60.7%;COX-2与Survivin、bcl-2表达呈正相关(r=0.5072、0.3783,均P<0.01).在肿瘤COX-2强表达组,紫杉醇(PTX)、表阿霉素(eADM)、羟基喜树碱(OPT)对肿瘤细胞抑制率明显低于弱表达组(均P<0.05);p53强表达与PTX、顺铂(DDP)对肿瘤细胞的抑制率明显降低有关(均P<0.05);Survivin强表达时,长春新碱(VCR)、DDP对肿瘤细胞抑制率明显降低(均P<0.05);bcl-2强表达时,5-氟尿嘧啶(5-Fu)、VCR、eADM、奥沙利铂(OXA)对肿瘤细胞抑制率明显低于弱表达组(均P<0.05).结论 消化道肿瘤COX-2通过抑制肿瘤细胞凋亡参与了肿瘤的多药耐药.     

COX-2、NSAIDs与肝癌

COX-2 mRNA和蛋白在HCC中呈普遍的高表达.COX-2可通过其抗凋亡、细胞周期阻滞、促进肿瘤细胞生长和肿瘤新生血管生成在HCC发生、发展过程中发挥作用.COX-2是防治HCC的重要分子靶点,大量的体内外实验证实NSAIDs能通过多种机制抑制HCC细胞的生长.     

选择性环氧化酶-2抑制剂的抗乳腺癌作用途径

环氧化酶(COX)-2在乳腺癌中呈过度表达，非甾体抗炎药(NSAIDs)通过抑制COX-2干扰致癌作用，但并不是唯一机制。为此，我们选择不表达COX-2的MCF-7乳腺癌细胞株，探讨选择性COX-2抑制剂nimesulide是否通过抑制NF(核因子)-KB的激活，促进肿瘤细胞的凋亡，以探讨其抗肿瘤的作用机制。     

环氧化酶-2与乳腺癌关系的研究现状及进展

环氧化酶2(cycloxygenase-2,COX-2)在人类多种肿瘤的发生发展过程中起着重要作用,其在乳腺癌中也存在着过度表达.因此,进一步深入研究COX-2与乳腺癌的关系,开发理想的COX-2抑制剂,以期开辟乳腺癌防治的一条新途径.     

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.     

环氧化酶-2在膀胱肿瘤中的研究进展

环氧化酶-2(COX-2)是环氧化酶的诱导型,是前列腺素(PGs)合成过程中的一个重要限速酶。近年来,COX-2在膀胱癌的发生发展方面的研究日益深入,有望成为膀胱癌防治的一个新靶点。本文就其生物学特点及在膀胱癌中的研究现状及COX-2抑制剂在膀胱癌防治中的应用前景进行综述。     

Role of cyclooxygenase-2 in breast cancer

Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandin H2, is expressed in normal brain and kidney, activated macrophages, synoviocytes during inflammation, and malignant epithelial cells. COX-2 expression is stimulated by a number of inflammatory cytokines, growth factors, oncogenes, lipopolysaccharides, and tumor promoters. There is evidence that COX-2 plays a key role in tumorigenesis through stimulating epithelial cell proliferation, inhibiting apoptosis, stimulating angiogenesis, enhancing cell invasiveness, mediating immune suppression, and by increasing the production of mutagens. Results of several studies using mouse models of colon cancer and the results of clinical trials have shown COX-2 to be a useful target for the prevention and treatment of colon cancer. Studies with several other epithelial cancers involving different organ sites, e.g., breast, prostate, bladder, lung, and pancreas, suggest that COX-2 plays an important role in the pathogenesis of these cancers. In this review, we summarize the studies that pertain to the involvement of COX-2 in breast cancer. COX-2 overexpression affects the physiological processes at different organ sites in a similar manner, although specific effectors and targets of COX-2 may differ at different sites. Thus in reviewing the data on the involvement of COX-2 in breast cancer, we have also considered the findings regarding the role of COX-2 in other organ sites. Studies from mouse models of mammary tumorigenesis and from human breast cancer cell lines provide evidence that COX-2 overexpression plays an important role in the pathogenesis of malignant breast cancer in humans. Because of availability of effective and relatively safe COX-2 inhibitors, it should be soon possible to evaluate their effectiveness in the clinic for the prevention and treatment of breast cancer. It is likely that the COX-2 inhibitors will be effective in the treatment regimens involving combination chemotherapies.     

COX-2 induces IL-11 production in human breast cancer cells

BACKGROUND: Cyclooxygenase-2 (COX-2) is overexpressed in 40% of human invasive breast cancers. Interleukin-11 (IL-11), a potent mediator of osteoclastogenesis, is involved in breast cancer metastasis to bone. Since breast cancers that overexpress COX-2 are associated with a higher rate of metastasis to bone, we hypothesized that COX-2 expression in tumor cells would induce IL-11. MATERIALS AND METHODS: We transfected MCF-7 (poorly metastatic) and MDA-231 (highly metastatic) human breast cancer cell lines with COX-2 expression vectors. COX-2 overexpression was confirmed by Western blot and PGE(2) immunoassay, and IL-11 production was measured by immunoassay. We also used a nude mouse model to study COX-2 and IL-11 production from breast cancer cells that metastasized to bone. The bone-seeking clones (BSC) were isolated and cultured from the long bone metastases. RESULTS: COX-2 transfection caused an approximately 5- to 6-fold increase in IL-11 production in both MCF-7 and MDA-231 cells. MDA-435S-COX2-BSC (cells isolated from bone metastasis) produced elevated levels of IL-11 and PGE2 (an important mediator of COX-2) as compared to the parental MDA-435S-COX2 cells. Furthermore, a treatment with low 1- to 2-microm concentration NS-398 or Celecoxib significantly reduced the production of IL-11 in COX-2-transfected MDA-231 cells, thus confirming the involvement of COX-2 in IL-11 induction. CONCLUSION: COX-2-mediated production of IL-11 in breast cancer cells may be vital to the development of osteolytic bone metastases in patients with breast cancer, and a COX-2 inhibitor may be useful in inhibiting this process.     

乳腺癌组织中COX-2、VEGF-C表达与淋巴转移的相关性研究

目的 探讨COX-2、VEGF-C在人乳腺癌组织中的表达及其与淋巴转移之间的关系.方法 运用免疫组织化学SABC法检测COX-2和VEGF-C在乳腺癌组织中的表达情况.结果 60例乳腺癌组织中COX-2和VEGF-C的表达阳性率分别为66.7%和60.0%,且二者表达呈正相关(r=0.429,P<0.05).COX-2阳性、VEGF-C阳性组淋巴转移的发生率(80.0%)明显高于COX-2阴性、VEGF-C阴性组(21.4%;P<0.05).结论 COX-2、VEGF-C在乳腺癌组织中呈过表达,呈正相关关系,且与乳腺癌的淋巴转移关系密切,COX-2表达上调可能促使VEGF-C的过表达,诱导肿瘤淋巴管的生成,从而导致乳腺癌细胞淋巴转移的发生.     

Role of COX-2 specific inhibitors in oncogenesis

Cyclooxygenase-2 (COX-2) is over expressed in a variety of premalignant and malignant conditions. It may contribute to carcinogenesis by modulating xenobiotic metabolism, apoptosis, immune surveillance, and angiogenesis. Selective COX-2 inhibitors suppress the formation of tumors in experimental models. Selective COX-2 inhibitors also suppress the growth and metastases of established tumors and enhance the anticancer activity of both radiotherapy and chemotherapy in experimental animals. This review aims at discussing evidence that inhibition of COX-2 represents a promising strategy to treat, prevent or possibly prevent human malignancies. Importantly, selective COX-2 inhibitors do not inhibit platelet function and cause fewer gastrointestinal side effects (peptic ulcer disease) than traditional nonsteroidal anti-inflammatory drugs (NSAIDS). More clinical trials are warranted to define the role of selective COX-2 inhibitors in the prevention and treatment of cancer along with their assessment of toxicity.     

Prophylaxis of colorectal cancer with non steroidal anti-inflammatory drugs- a new reality?

The use COX-2 inhibitors induces regression of adenoma polyps and disrupts the sequence adenoma colorectal carcinoma. So that, this can be used in chemoprevention of colorectal cancer and also in cancer localised in other segments of the digestive tract. So far there is no agreement regarding the beginning of the treatment, the minimal efficient dose, the span of time required for chemoprevention. As the current studies in this field are quite encouraging we believe that in the next future COX-2 inhibitors could be used not only in chemoprevention but also in tumoral regression, and as a codrug in chemiotherapy of colorectal cancer.     

Induction of apoptosis by cyclooxygenase-2 inhibitors in prostate cancer cell lines

Prostaglandins are thought to play an important role in the proliferation of prostate cancer and are highly expressed in prostate cancer tissue. Cyclooxygenase-2 (COX-2), or prostaglandin endoperoxide synthase, is a key enzyme in the conversion of arachidonic acid into prostaglandin. In several cancers, COX-2 contributes to the proliferation and metastasis of cancer cells. To assess the role of COX-2 in prostate cancer, we investigated whether the inhibition of COX-2 affected the proliferation of prostate cancer cells. The human prostate cancer cell lines, LNCaP and PC 3, and a normal prostate stromal cell line (PrSC) were treated with COX-2 inhibitors NS 398 and Etodolac. The proliferation rate of the cell lines was examined using 3(4,5-dimethylethiazoly 1-2-) 2,5-diphonyl tetrazolium bromide (MTT) assays. A DNA fragmentation assay was also used for proof of apoptosis. COX-2 inhibitors could suppress the proliferation of LNCaP and PC 3 cells. In contrast, PrSC was not affected by COX-2 inhibitors. These suppressive effects occurred in a time- and dose-dependent manner. One of mechanisms responsible for cell death was apoptosis. COX-2 seems to play a significant role in the progression of prostate cancer. COX-2 may be a therapeutic target for prostate cancer. Since COX-2 inhibitors suppress proliferation and induce apoptosis in prostate cancer cells, and have no effect in normal prostate stromal cells, COX-2 inhibitors will be useful for the treatment of prostate cancer.     

胃肠间质瘤合并消化道癌六例诊治体会

目的 探讨胃肠间质瘤合并消化道癌的临床特征、诊治及预后.方法 回顾性分析武汉协和医院2005年1月-2010年9月收治的6例胃肠间质瘤合并消化道癌的临床病理资料.结果 6例患者中有4例2种肿瘤发生在同一脏器,2例发生于相邻器官.术前检查只有1例发现胃肠间质瘤与消化道癌同时存在,其余5例只发现消化道癌.6例患者中胃肠间质...     

胃肠道间质瘤的诊治现状与进展

目的总结胃肠道间质瘤（GIST）的发病机制及流行病学特点,探讨其诊断及治疗并分析其预后。方法复习与GIST的发病机制、流行病学、诊断、治疗及预后方面有关的文献并对其进行综述。结果 GIST为非上皮源性肿瘤,起源于Cajal间叶细胞,是消化道最常见的间叶性肿瘤,约占消化道肿瘤的1%～3%,中位发病年龄为40～60岁,胃为最好发部位。目前认为,GIST的发病机制与原癌基因c-kit或血小板源性生长因子受体α（PDGFRα）基因突变有密切关系,但PDGFRα和c-kit基因突变不会同时出现在同一患者中。GIST的临床表现缺乏特异性,临床诊断主要依靠内镜及影像学技术,最终确诊依靠病理学检查。目前对GIST的治疗以手术与分子靶向药物治疗为主,其预后与肿瘤危险度分级及治疗干预密切相关。结论 GIST是具有恶性潜能的肿瘤,其危险度分级是指导临床治疗及预后评估的重要指标,GIST的预防、诊断、治疗及复发的预防有待进一步研究。     

Involvement of IL-8 in COX-2-mediated bone metastases from breast cancer

BACKGROUND: Cyclooxygenase-2 (COX-2) overexpression by a primary tumor correlates with poor prognosis in breast cancer, including early spread to bone. Interleukin-8 (IL-8) stimulates osteoclastogenesis and resorption of bone, and elevated IL-8 levels predict early metastatic spread of breast cancer. The purpose of this study was to test our hypothesis that tumors that overexpress COX-2 induce IL-8 production. MATERIALS AND METHODS: We cotransfected MCF-10A (nonmalignant breast epithelial) cells, as well as MDA-231 (highly metastatic human breast cancer) cell lines with a pSG5-COX-2 vector and pEF1a-Luc-IRES-Neo vector (luciferase reporter). COX-2 overexpression was confirmed by Western blot and PGE2 (a product of the COX-2 pathway) immunoassay. IL-8 production was measured by immunoassay. In vivo testing used a nude mouse model to measure COX-2 and IL-8 production from breast cancer cells that had metastasized to bone (bone-seeking clones (BSCs)). Long bone metastases were localized and quantified by luciferase imaging (Xenogen IVIS system) and X-ray. BSCs were isolated and cultured and then tested for the production of PGE2 and IL-8. RESULTS: COX-2 overexpression caused a 4- to 5-fold increase in IL-8 production in both MCF-10A and MDA-231 cells in vitro. In vivo, we observed that the MDA-231-BSC (metastatic cells isolated from bone metastases) produced significantly greater levels of both PGE2 and IL-8 compared to the parental MDA-231 cells (P < 0.01). In contrast to the results obtained with these estrogen receptor-negative cell lines, COX-2 expression failed to induce IL-8 in the MCF-7 estrogen receptor-positive breast cancer cell line. Treatment with the COX-2 inhibitor NS-398 at a low 1-mu[scap]M dose reduced the production of IL-8 in COX-2-transfected MDA-231 cells by 30%, thus confirming the involvement of COX-2 in IL-8 induction. CONCLUSION: COX-2 expression induced formation of PGE2 and IL-8 in breast cancer cells. Since PGE2 and IL-8 stimulate osteoclasts to resorb bone, COX-2 inhibition is a potential target for treatment to prevent bone metastases.     

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.