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1.
《Expert opinion on investigational drugs》2013,22(8):1225-1235
Background: Glioblastoma multiforme (GBM), a highly invasive and vascular cancer, responds poorly to conventional cytotoxic therapy. Integrins, widely expressed in GBM and tumor vasculature, mediate cell survival, migration and angiogenesis. Cilengitide is a potent αvβ3 and αvβ5 integrin inhibitor. Objective: To summarize the preclinical and clinical experience with cilengitide for GBM. Methods: Preclinical studies and clinical trials evaluating cilengitide for GBM were reviewed. Results/conclusions: Cilengitide is active and synergizes with external beam radiotherapy in preclinical GBM models. In clinical trials for recurrent GBM, single-agent cilengitide has antitumor benefits and minimal toxicity. Among newly diagnosed GBM patients, single-arm studies incorporating cilengitide into standard external beam radiotherapy/temozolomide have shown encouraging activity with no increased toxicity and have led to a planned randomized Phase III trial. 相似文献
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目的研究胃癌组织中PTEN蛋白、血管内皮生长因子(VEGF)表达和血管形成的关系。方法采用免疫组织化学S-P法检测20例正常胃黏膜及80例胃癌组织中PTEN、VEGF、微血管密度(MVD)的表达。结果20例正常胃黏膜组织PTEN全部阳性表达,胃癌组织PTEN阳性率为52.5%(40/80)、PTEN蛋白表达水平与组织分化程度、淋巴结转移及TNM分期密切相关(P〈0.05),VEGF在正常胃黏膜阳性率为10%(2/20),胃癌组织阳性率为53.8%(43/80),二者差异有显著性(P〈0.01),VEGF表达与淋巴结转移及TNM分期密切相关(P〈0.05),胃癌组织MVD显著高于正常胃黏膜MVD(P〈0.01),MVD与胃癌组织浸润深度、分化程度、淋巴结转移及TNM分期密切相关(P〈0.01),胃癌组织中VEGF表达与MVD呈显著正相关(P〈0.01),PTEN蛋白表达水平与VEGF表达呈显著负相关(P〈0.01),PTEN蛋白表达水平与MVD呈显著负相关(P〈0.01)。结论PTEN蛋白表达与胃癌的临床病理特征密切相关,胃癌PTEN基因失活可能通过增加VEGF的表达来促进血管形成,导致肿瘤恶性进展。 相似文献
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《Expert opinion on pharmacotherapy》2013,14(2):219-226
Therapeutic angiogenesis is a promising treatment for ischaemic heart disease, particularly for patients who are not candidates for current methods of revascularisation. The goal of angiogenic therapy is the relief of symptoms of coronary artery disease and improvement of cardiac function by increasing perfusion to the ischaemic myocardium. Angiogenic cytokines such as fibroblast growth factor and vascular endothelial growth factor have been studied extensively in preclinical studies. Protein-based therapy with these growth factors has produced functionally significant angiogenesis in several animal models. Enthusiasm following these preclinical results led the way to clinical trials, which so far have shown only modest improvements in myocardial perfusion and clinical outcome. The attenuated angiogenic response to growth factor therapy observed in patients with coronary artery disease may be related to associated conditions such as endothelial dysfunction, regimens of single as opposed to multiple angiogenic agents and inefficiency of current delivery modalities, as illustrated by the disappointing results of the Phase II clinical trials using intravascular techniques of administration. The ultimate role angiogenesis will play clinically in the treatment of ischaemic heart disease will be determined by adequately powered, randomised, double-blind, placebo-controlled trials that include multi-agent angiogenic therapy and intramyocardial methods of delivery. 相似文献
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贝伐单抗对肝癌细胞株HepG2增殖的抑制作用 总被引:1,自引:0,他引:1
目的通过体外实验探讨贝伐单抗(bevacizumab)对人肝癌细胞HepG2增殖的抑制作用及可能的分子机制。方法MTT法检测贝伐单抗对肝癌细胞增殖的抑制作用;流式细胞仪检测细胞凋亡;RT-PCR分析肝癌细胞株VEGF、Flt-1、KDR mRNA表达量的变化。结果不同质量浓度的贝伐单抗对肝癌细胞株HepG2的增殖有抑制作用;贝伐单抗可诱导肝癌细胞株HepG2的凋亡;贝伐单抗作用于肝癌细胞株HepG2后,其VEGF、KDR mRNA表达量均减少。结论贝伐单抗可能通过阻断VEGF的促增殖作用而抑制HepG2细胞增殖。 相似文献
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本研究采用斑马鱼胚胎模型研究力达霉素在整体动物水平对血管生成的影响。力达霉素处理胚胎后, 利用形态学观察、血管染色法、转基因斑马鱼检测其对胚胎血管生成影响, 以荧光定量PCR和蛋白免疫印迹法检测VEGF基因的表达情况。结果显示: 力达霉素处理后, 胚胎出现心包水肿、血流速度减缓等症状; 血管生长率降低, 肠下静脉生成受到抑制。荧光定量PCR和蛋白免疫印迹检测表明, 力达霉素对胚胎的VEGF mRNA表达水平没有影响, 但VEGF蛋白的表达受到显著抑制。研究结果表明, 力达霉素可以下调VEGF蛋白表达, 从而抑制斑马鱼胚胎血管生成。 相似文献
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《Expert opinion on investigational drugs》2013,22(6):703-705
In colorectal cancer, increased expression of the angiogenesis promoter vascular endothelial growth factor correlates with invasiveness, vascular density, metastases, recurrence and prognosis. Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor. In recent clinical trials, bevacizumab has been shown to prolong the time to disease progression and the survival of patients with colorectal cancer. In six patients with adenocarcinoma of the rectum, bevacizumab decreased tumour blood perfusion and volume, interstitial fluid pressure, the number of circulating endothelial cells and fluorodeoxyglucose uptake. Surgical specimens showed a marked response in all six patients with only microscopic disease in five of the patients. These effects of bevacizumab on the vascular biology of tumours probably underlie the progression and survival benefits observed in clinical trials of colorectal cancer. 相似文献
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《Expert opinion on investigational drugs》2013,22(4):467-476
Pancreatic cancer is the fourth leading cause of cancer-related deaths in Western countries and is among the deadliest diseases in humans. At present, gemcitabine is the standard chemotherapy for advanced pancreatic cancer, although (despite its use) prognosis continues to be dismal with a median survival of < 6 months. While targeting tumor vasculature has provided improved outcomes in colon, lung, breast and renal cell cancers, trials of angiogenesis inhibitors have lagged behind in pancreatic cancer. This review provides the rationale for exploring antiangiogenic therapies in the treatment of pancreatic cancer as well as summarizes present clinical development of VEGF receptor tyrosine kinase inhibitors and their application to pancreatic cancer. 相似文献
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Angiogenesis refers to the process of remodeling the vascular tissue characterized by the branching out of a new blood vessel from a pre-existing vessel. Angiogenesis is particularly active during embryogenesis, while during adult life it is quiescent and limited to particular physiologic phenomena. Recently, the study of molecular mechanisms of angiogenesis has stirred renewed interest due to the recognition of the role played by angiogenesis in several pathologies of significant medical impact, such as cancer and cardiovascular disease, and due to the pharmacologic interest rising from the possibility of modulating these phenomena. Antibodies, peptides and small molecules targeting active endothelial cells represent an innovative tool in therapeutic and diagnostic fields. In this study, we reviewed the literature of peptide and peptidomimetics in angiogenesis and their potential applications. Two specific protein systems, namely the vascular endothelial growth factor and its receptor and integrins, will be discussed in detail. 相似文献
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目的 研究注射用丹参多酚酸(SAFI)对氧糖剥夺/复氧复糖(OGD/R)损伤后小鼠脑微血管内皮细胞(BEND3)增殖、迁移、成管能力的影响及机制。方法 CCK-8法检测SAFI对正常BEND3细胞活力的影响,筛选出安全作用浓度。取正常生长的对数期BEND3细胞,分为对照组、模型组、SAFI(0.63、1.25、2.50、5.00、10.00 μg·mL-1)组,模型组与SAFI组建立OGD/R模型,缺氧缺糖4 h、复氧复糖24 h;CCK-8法检测BEND3细胞活力;划痕实验检测BEND3细胞迁移能力;基质胶成管实验检测BEND3细胞成管能力;Western blotting法检测BEND3细胞血管内皮生长因子A(VEGFA)、血管生成素-1 (Ang-1)、Ang-2蛋白表达。结果 与对照组比较,模型组细胞活力、细胞迁移率及细胞成管血管网络的交叉点数、节点数、分支点数、血管总长度均显著降低(P<0.05、0.01);与模型组比较,SAFI浓度为2.50、5.00、10.00 μg·mL-1时细胞活力、细胞迁移率及细胞成管血管网络的交叉点数、节点数、分支点数、血管总长度、网眼总面积和VEGFA和Ang-1、Ang-2蛋白表达量均显著上升(P<0.05、0.01),且作用呈浓度相关性。结论 SAFI可提高BEND3细胞OGD/R损伤后的增殖能力、迁移能力、成管能力,机制可能与上调VEGFA和Ang-1、Ang-2蛋白表达相关。 相似文献
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《Expert opinion on therapeutic targets》2013,17(6):867-876
Angiogenesis plays an important role in the formation of new blood vessels and is crucial for tumour development and progression. Imbalance between pro- and antiangiogenesis factors regulates the biological process of angiogenesis. The best characterised of the proangiogenic factors and the most potent is vascular endothelial growth factor (VEGF). The binding of VEGF to one of its transmembrane tyrosine kinase receptors, which are predominantly found on endothelial cells, results in receptor dimerisation, activation and autophosphorylation of the tyrosine kinase domain. This triggers a cascade of complex downstream signalling pathways. Several strategies targeting the VEGF signalling pathway have been developed. These include neutralising antibodies to VEGF (bevacizumab) or VEGF receptors (VEGFRs) (DC101), soluble VEGFR/VEGFR hybrids (VEGF-Trap), and tyrosine kinase inhibitors of VEGFRs (BAY43-9006, SU11248, ZD6474, AZD2171, PTK/ZK and others). Several of these agents are now being investigated in clinical trials. 相似文献
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姜黄素抑制子宫内膜异位症血管形成的实验研究 总被引:1,自引:0,他引:1
目的:观察姜黄素对大鼠子宫内膜异位症(endometriosis,EMs)局部血管形成的影响和抗血管形成作用。方法:制作Wistar大鼠EMs动物模型,4周后将大鼠分为正常组、假手术组、模型组、姜黄素低剂量组及姜黄素高剂量组5组,持续用药28d,SP免疫组化法测定在位内膜和异位组织灶中微血管密度(microvessel density,MVD)的表达,western blotting测定局部血管内皮生长因子(vascular endothelial growth factor,VEGF)蛋白量的表达。结果:姜黄素治疗模型大鼠EMs,4周后异位组织中MVD和VEGF蛋白量的表达明显低于模型组,差异有显著性(P<0.05),而在位内膜中MVD的表达与模型组相比,差异无显著性(P>0.05);姜黄素可剂量依赖性的抑制EMs异位组织的增生。结论:姜黄素对子宫内膜异位症大鼠异位组织中MVD的表达和VEGF蛋白的表达均有抑制作用,作用呈剂量依赖性。姜黄素有望成为子宫内膜异位症抗血管形成治疗的新药。 相似文献
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《Expert opinion on therapeutic targets》2013,17(3):323-332
Balanced regulation of endothelial cell function and co-ordination of endothelial cells and periendothelial support cells by angiogenic growth factors and cell type-specific receptor tyrosine kinases is crucially involved in physiological angiogenesis. Disturbance of this fine-tuned balance is associated with disease-related neoangiogenesis, such as in tumour angiogenesis or in retinopathy, or in insufficient angiogenesis in occlusive vascular disease. In addition to the well known function of vascular endothelial growth factor (VEGF) as an endothelial cell-specific angiogenesis inducer and survival factor, recent studies on angiopoietins and their receptors have provided insight into the interplay of these endothelium-specific ligand-receptor systems in formation, maintenance and remodelling of the vasculature. Knowledge of the mechanisms by which these ligand-receptor systems are involved in regulation of the interaction of endothelial cells and their periendothelial support cells opens new opportunities for therapeutic angiogenesis to induce formation of functional blood vessels in occlusive disease, as well as to complement and/or enhance current anti-VEGF-based strategies for anti-angiogenic therapy. 相似文献
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Development of angiogenesis inhibitors for cancer therapy 总被引:1,自引:0,他引:1
Abundant literature exists demonstrating that tumors are dependent on angiogenesis for both tumor growth and invasion. The extent of angiogenesis in primary tumors has been demonstrated to be associated with a negative prognosis in several tumors including non-small cell lung carcinoma, prostate cancer, and in node-negative breast cancer, where angiogenesis is an independent negative prognostic factor. These data demonstrate the significance of angiogenesis in tumor biology and indicate that it can be utilized as a target for novel therapeutic strategies. The recent expansion of knowledge into the specific pathways of tumor angiogenesis has provided reagents which can now be utilized to provide markers of efficacy of antiangiogenic agents in cancer patients. A critical part of the development of angiogenesis inhibitors for cancer therapy is the clinical trial strategy. Since these agents are primarily thought to be cytostatic, carefully designed trials must be conducted which focus on appropriate endpoints and integrate relevant biologic markers to support efficacy. 相似文献
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The effects of cadmium on VEGF-mediated angiogenesis in HUVECs 总被引:1,自引:0,他引:1
Kim J Lim W Ko Y Kwon H Kim S Kim O Park G Choi H Kim O 《Journal of applied toxicology : JAT》2012,32(5):342-349
Cadmium (Cd) is a highly toxic element that causes morphologic alterations and dysfunction in blood vessels. The altered vascular function caused by cadmium has been implicated in a range of chronic diseases, including hypertension. The effects of cadmium are a multisystem phenomenon involving inflammation, hypertrophy, apoptosis, angiogenesis and important processes involved in vascular remodeling systems. Vascular endothelial growth factor (VEGF) plays a major role in cell growth and angiogenesis under pathologic conditions. VEGF secretion is related to anti-apoptosis protein expression and attenuates apoptosis in endothelial cells. This study examined the VEGF-dependent mechanisms of angiogenesis and apoptosis in cadmium-treated endothelial cells (HUVECs). The effects and mechanisms of cadmium in endothelial cells (HUVECs) were examined by exposing the cells to different doses of cadmium chloride (2.5-40 μ m). After the cadmium treatment, the angiogenesis and apoptosis mechanisms related to VEGF in cadmium-treated HUVECs were examined. As a result, the low concentration of cadmium increased the tube formation in HUVECs. In addition, cadmium at concentrations of 5 and 10 μ m increased VEGF secretion and VEGFR2 activity, which suggest that cadmium affects the growth of blood vessels. All three MAPK pathways, namely ERK, JNK and p38, were activated by cadmium in HUVECs. However, high concentrations of cadmium caused cell damage, disrupted tube formation and inhibited VEGF expression and the activities of VEGFR2 and MAPK in HUVECs. Cadmium has dual functions through VEGF-dependent mechanisms in a dose-dependent manner. In this study, the dual effects of cadmium might alter angiogenesis and induce apoptosis through VEGF pathways in HUVECs. 相似文献
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《Expert opinion on therapeutic patents》2013,23(12):1695-1706
Vascular endothelial growth factor (VEGF) is the prototype of a subfamily of five growth factors sharing structural homologies with the platelet-derived growth factor (PDGF) protein superfamily. The VEGFs are potent mitogens specific for endothelial cells of the blood or lymphatic vasculature and are effective modulators of vessel permeability in the normal physiological processes of angiogenesis and vasculogenesis. VEGF appears to be a significant promoter of the inappropriate angiogenesis that sustains tumour growth and metastasis, inflammatory joint disease and diabetic retinopathy. Understanding the cell biology and control of VEGF expression has led to the development of several strategies for antagonising the pathological angiogenesis associated with these common diseases. This review describes these promising approaches in the context of current understanding of VEGF biology. 相似文献
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目的探讨大鼠创伤性脑损伤后血管内皮生长因子(VEGF)和内皮抑素(ES)的动态变化及同神经评分的相关性。方法 SD大鼠140只随机分为正常对照组(n=20)、假手术组(n=20)和脑损伤组(n=100),采用Marmarou法建立脑损伤模型,脑损伤组在损伤后1,6,12,24和72 h各取20只进行神经功能评分,酶联免疫吸附(ELISA)法检测脑组织中VEGF和ES水平。结果创伤性脑损伤后脑组织VEGF含量1~12 h无变化,24 h开始显著上升;ES含量1~24 h无变化,72 h开始显著上升;重度脑损伤大鼠VEGF和ES水平较中度损伤大鼠升高早,幅度大。结论创伤性脑损伤大鼠脑组织VEGF和ES含量随损伤时间呈规律性动态变化,和神经功能评分的变化趋势相符,可能同自身修复存在相关性。 相似文献
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《Expert opinion on therapeutic targets》2013,17(10):1047-1057
Importance of the field: The role of angiogenesis in the initiation and progression of NSCLC and the molecular alterations leading to the growth of tumor vasculature are areas of great interest and recent therapeutic success.Areas covered in this review: VEGF and its receptors play critical roles in the development of tumor vasculature and can be targeted by agents such as bevacizumab in the treatment of NSCLC. Furthermore, tumor hypoxia and the expression of the hypoxia-inducible factor (HIF) family of proteins are also linked to poorer survival in these patients. Recent studies using genetically engineered mouse models expressing stabilized HIF validate the importance of HIF in the evolution of NSCLC and demonstrate genetically that HIF is involved in NSCLC.What the reader will gain: An overview of the key pathways and mediators of tumor angiogenesis, their relevance to the pathogenesis of NSCLC, and an update on the current status of angiogenesis inhibitors in NSCLC.Take home message: Angiogenesis is a key mediator of NSCLC progression. Several antiangiogenic strategies are in clinical use and under development. While candidate predictive biomarkers of response to antiangiogenic therapy exist, they await independent and prospective validation. 相似文献