Antiangiogenic agents targeting vascular endothelial growth factor and its receptors in clinical development

There is ample therapeutic opportunity for the use of antiangiogenic inhibitors in the clinic, as there are several human diseases that are dependent upon angiogenesis [1]. However, no disease has attracted as much attention as a target for antiangiogenic therapy as malignant disorders. There is a vast amount of literature acting as proof-of-principle for the use of angiogenic inhibitors as effective agents for blocking tumour-induced angiogenesis and subverting tumour growth and disease dissemination. One of the unique attractions of targeting tumour angiogenesis is that vascular endothelial cells are a genetically stable population in which acquisition of therapeutic resistance might be less efficient than in genetically unstable tumour cells [2,3]. This review covers inhibitors that target the tumour angiogenic agent vascular endothelial growth factor and its receptors as one such antiangiogenic approach. Many agents in this class are in clinical trials with limited reports of toxicity and some early evidence of clinical benefit.     

Clinical development of angiogenesis inhibitors to vascular endothelial growth factor and its receptors as cancer therapeutics

Angiogenesis, the formation of new blood vessels, is essential for both tumor growth and metastasis. Recent advances in our understanding of the molecular mechanisms underlying the angiogenesis process and its regulation have led to the discovery of a variety of pharmaceutical agents with anti-angiogenic activity. The potential application of these angiogenesis inhibitors is currently under intense clinical investigation. Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play critical roles in tumor-associated angiogenesis, and that they represent potential targets for therapeutic intervention. This has been demonstrated in a variety of animal tumor models in which disabling the function of VEGF and its receptors was shown to inhibit both tumor growth and metastasis. A number of agents designed specifically for targeting VEGF and/or its receptors are being evaluated in various clinical trials in cancer patients. This review will discuss the biology of the VEGF and its receptors, the mechanisms of action as well as the current status in clinical development of antagonistic agents to VEGF and its receptors. Included in this review are antagonistic antibodies, ribozymes, immunotoxins, and synthetic small molecular inhibitors.     

血管内皮生长因子及受体在急性白血病中的表达及临床意义

目的：探讨血管生成在急性白血病（AL）发病、预后中的作用。方法：应用免疫组化法检测30例初治AL患诱导化疗前后骨髓中微血管密度（MVD）、血管内皮生长因子（VEGF）及受体KDR、Flt-l变化与临床特征的关系。结果：初治AL患骨髓组织中KDR、VEGF和MVD的表达高于对照组（P＜0．05）；完全缓解（CR）后MVD及VEGF阳性率明显下降；未完全缓解（NR）组的MVD及VEGF阳性率有治疗前无显性下降（P＞0．05）；Kaplan-Meier分析显示治疗前VEGF阴性组的生存时间大于VEGF阳性组（P＜0．05）。结论：AL骨髓中存在血管生成，VEGF与AL的发病及预后有关。     

Antiangiogenic therapy in acute myelogenous leukemia: targeting of vascular endothelial growth factor and interleukin 8 as possible antileukemic strategies

Acute myelogenous leukemia (AML) is an aggressive disorder with an overall disease-free survival of 40-50% even for the younger patients under 60 years of age who can receive the most intensive treatment. The median age at the time of diagnosis is 60-65 years, and the large majority of elderly patients usually receive less intensive chemotherapy or only supportive therapy due to the high treatment-related mortality when using intensive therapy for elderly individuals. Thus, there is a need for new therapeutic approaches to improve the treatment in younger patients and to make AML-directed therapy with acceptable toxicity possible in elderly individuals. Angiogenesis seems to be important both for leukemogenesis and susceptibility to intensive chemotherapy, and antiangiogenic strategies are therefore considered for the treatment of AML. The two proangiogenic mediators vascular endothelial growth factor (VEGF) and interleukin 8, (IL-8, also referred to as CXCL8) seem to be important in human AML: VEGF is released at increased levels due to interactions between AML cells and neighboring nonleukemic cells, whereas IL-8 is released at high levels by native human AML cells. Thus, VEGF as a therapeutic target in AML is suggested both by experimental and clinical observations, whereas IL-8 as a target is mainly suggested by experimental evidence. In the present review we describe and discuss (i) the angioregulatory network of soluble mediators in AML, including both the systemic levels and local release by native human AML cells; and (ii) various therapeutic approaches to target VEGF and IL-8. Although single angioregulatory mediators can be targeted, it should be emphasized that the final effect of soluble mediators on angioregulation is determined by a complex angioregulatory network that varies between AML patients, and the final effect of targeting single mediators may therefore differ between patient subsets.     

血管内皮生长因子受体在胶质瘤中的表达

目的 研究人脑胶质瘤组织中血管内皮生长因子受体(KDR、Flt-1)mRNA的表达,同时分析肿瘤间质血管增生的情况,并探讨两之间的关系。方法 采用半定量逆转录-聚合酶链反应(RT-PCR)方法,对49例人脑胶质瘤手术切除标本,U251等3株胶质瘤细胞、人类脐静脉内皮细胞(HUVEC)以及12例脑外伤内减压术中得到的正常脑组织检测了KDR、Flt-1 mRNA表达水平。另外,用免疫组化SP法对胶质瘤及正常脑组织的微血管密度(MVD)进行了分析。结果 胶质瘤组织中的KDR、Flt-1 mRNA表达水平明显增高,分别达59．2％、63．2％,随着病理分级的提高其表达水平有升高趋势,HUVEC及3株胶质瘤细胞亦表达水平较高。胶质瘤中的微血管密度(MVD)与胶质瘤级别有关,KDR、Flt-1 mRNA的表达同MVD呈正相关。结论 KDR、Flt-1、MVD对胶质瘤的恶性生物学行为评估有重要意义,血管内皮生长因子受体的高表达与肿瘤组织血管增生有关,在胶质瘤侵袭过程中发挥重要作用。     

造血细胞表达血管内皮生长因子及其受体基因的研究

目的 探控血管内皮生长因子（VEGF）及其受体Flt-1和KDR基因在造血细胞中的表达。方法 提取正常外周血、骨髓单个核细胞及血液肿瘤细胞系的总RNA,以β2-微球蛋白基因为内标,用单定量逆转录聚合酶链反应（RT-PCR）分析VEGF,Flt-1和KDR基因的表达。结果 在22份正常外周血和22份非恶性骨髓标本中,分别有18份和19份表达,VEGF基因,而10种人类血液肿瘤细胞系均有VEGF基因的高度表达。在12份外周血中,有4份检测到Flt-1基因表达,但均未见有KDR基因表达;在22份骨髓中,分别有9份和14份表达Flt-1基因或KDR基因。10种血液肿瘤细胞系有6种表达Flt-1基因,而KDR基因表达仅见于Raji细胞。血小板也有VEGF和Flt-1基因的低度表达。结论 VEGF作为血管生成的介导物,可能具有调节正常造血细胞和血液肿瘤细胞生长的作用。     

Inhibitors targeting hepatocyte growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases

Amgen disclosed a series of 4-heteroaryloxy quinoline/quinazoline compounds as multiple kinase inhibitors, including hepatocyte growth factor (HGF) receptor tyrosine kinase c-Met and vascular endothelial growth factor (VEGF) receptor tyrosine kinase. These compounds are stated to have wide therapeutic applications for the treatment of a variety of cancers, hypertension, arteriosclerosis, myocardial infarction and rheumatoid arthritis.     

Vascular endothelial growth factor and vascular endothelial growth factor receptor inhibitors as anti-angiogenic agents in cancer therapy

New blood vessel formation (angiogenesis) is fundamental to the process of tumor growth, invasion, and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of ligands and receptors are well established as key regulators of these processes. VEGF is a glycoprotein with mitogenic activity on vascular endothelial cells. Specifically, VEGF-receptor pathway activation results in signaling cascades that promote endothelial cell growth, migration, differentiation, and survival from pre-existing vasculature. Thus, the role of VEGF has been extensively studied in the pathogenesis and angiogenesis of human cancers. Recent identification of seven VEGF ligand variants (VEGF [A-F], PIGF) and three VEGF tyrosine kinase receptors (VEGFR- [1-3]) has led to the development of several novel inhibitory compounds. Clinical trials have shown inhibitors to this pathway (anti-VEGF therapies) are effective in reducing tumor size, metastasis and blood vessel formation. Clinically, this may result in increased progression free survival, overall patient survival rate and will expand the potential for combinatorial therapies. Having been first described in the 1980s, VEGF patenting activity since then has focused on anti-cancer therapeutics designed to inhibit tumoral vascular formation. This review will focus on patents which target VEGF-[A-F] and/or VEGFR-[1-3] for use in anti-cancer treatment.     

以血管内皮生长因子及其受体为靶点的肿瘤疫苗研究进展

肿瘤的生长、侵袭和迁移依赖于血管新生.因此,以抑制肿瘤血管形成为目标的抗肿瘤治疗策略是当前研究的热点.血管内皮生长因子及其受体在肿瘤血管新生这一病理性血管形成过程中起关键作用,从而使它们成为研发肿瘤疫苗的靶点.此文就疫苗的研发基础、免疫机制及研究进展做一综述.     

子宫内膜异位症患者血管内皮生长因子的检测及其临床意义

目的旨在探讨血管内皮生长因子(VEGF)在子宫内膜异位症(EM)发病机制中的作用,并初步探讨VECG在EM中的诊断价值。方法采用定量双抗体夹心酶联免疫吸附法(ABC-ELISA)测定44例EM患者(Ⅰ~Ⅱ期10例,Ⅲ期20例、Ⅳ期14例),20例对照组和18例术后经孕三烯酮治疗3个月的EM患者腹腔液和血清中VEGF的浓度。分析EM患者腹腔液中VEGF与EM r-AFS分期的关系,并比较VEGF在血清、腹腔液中的含量,同时利用ROC曲线初步分析其诊断EM的灵敏度和特异性。结果①EM患者腹腔液中VEGF浓度显著高于对照组(P<0.05);VEGF浓度在EM患者Ⅰ~Ⅱ期和Ⅲ期、Ⅳ期比较差异均无统计学意义(P>0.05);②EM患者血清中VEGF浓度高于复查组,差异有统计学意义(P<0.05);③ROC曲线发现,EM患者腹腔液中VEGF浓度对EM的诊断具有一定价值。结论VEGF在EM的发病机制中可能发挥着重要作用,抗血管生成治疗方法有望成为EM新的治疗策略和靶点。     

Antiangiogenic effect of silicate nanoparticle on retinal neovascularization induced by vascular endothelial growth factor

Angiogenesis-related blindness indicates the spectrum of retinal diseases that are caused by pathological angiogenesis, resulting in catastrophic vision loss. We aimed to demonstrate the antiangiogenic effect of silicate nanoparticles (SiNPs) on the retinal neovascularization. No direct toxicity of SiNPs was observed on retinal neuronal or endothelial cells, nor on the retinal tissue. Furthermore, intravitreal injection of SiNPs effectively reduced anomalous retinal angiogenesis in oxygen-induced retinopathy mice. SiNPs also effectively inhibited in vitro vascular endothelial growth factor (VEGF)-induced angiogenesis. Via suppression of VEGF receptor-2 phosphorylation induced by VEGF, SiNPs blocked ERK 1/2 activation. SiNPs could be an inhibitor of the potency and safety of retinal neovascularization that is mediated by VEGF and utilized in the treatment of angiogenesis-related blindness. FROM THE CLINICAL EDITOR: In this important preclinical study, silicate NP-s are studied to address retinal neovascularization, an important pathomechanism of different retinal diseases that could lead to catastrophic vision loss. The authors conclude that SiNP-s could be utilized as inhibitors of retinal neovascularization mediated by VEGF and propose future applications in the treatment of angiogenesis-related blindness.     

糖尿病视网膜病变患者血清PlGF和VEGF水平的变化及其临床意义

目的探讨糖尿病视网膜病变（DR）患者血清胎盘生长因子（P1GF）水平的变化及其临床意义。方法采用ELISA法检测51例DR患者血清P1GF和VEGF的变化,其中,非增生性DR（NPDR）22例,增生性DR（PDR）29例。并与54例非糖尿病视网膜病变（NDR）患者进行比较,同时以40例健康者作为对照。结果DR患者血清P1GF和VEGF水平明显高于对照组（t值分别为1．907和2．942,P〈0．05）;PDR患者P1GF和VEGF水平明显高于NPDR患者（t值分别为19．024和16．319,P〈0．05）。结论血清P1GF和VEGF水平变化参与了DR的发生与发展,且与病变严重程度有关。     

CD34血管内皮生长因子在胃癌中的表达及其临床意义

目的探讨胃癌组织中CD34、血管内皮生长因子(VEGF)的表达与其生物学行为的关系。方法应用免疫组织化学技术检测55例胃癌组织及癌旁胃黏膜组织中CD34、VEGF的表达情况,分析微血管密度(MVD)计数、VEGF表达与胃癌生物学行为的关系。结果胃癌组织中VEGF的表达、MVD计数均明显高于癌旁胃黏膜组织,差异具有统计学意义(P<0.05),且在胃癌组织中VEGF的表达与MVD计数呈正相关,r=0.728。MVD计数、VEGF的表达与胃癌胃壁浸润深度、局部淋巴结转移、近期远隔转移程度呈正相关,MVD计数在不同浸润深度、有无淋巴结转移、有无近期远隔转移各组间差异有统计学意义,不同分化程度各组间差异无统计学意义。结论胃癌组织中存在着肿瘤血管生成,在胃癌肿瘤血管生成的过程中VEGF发挥着重要的作用,且MVD计数、VEGF的表达可以反映胃癌的生物学行为。     

结肠癌患者血清血管内皮生长因子的表达及其临床意义

目的探讨血管内皮生长因子（VEGF）在结肠癌患者血清中的表达及临床意义。方法采用ELISA法检测56例结肠癌患者和23例正常对照者血清中VEGF的含量。结果结肠癌患者血清VEGF表达水平显著高于正常对照组,且远处转移患者血清VEGF水平明显高于无转移患者。结论血清VEGF表达的检测对结肠癌的诊断具有一定的临床意义,有助于反映结肠癌的进展和预后判断,且血清VEGF水平与结肠癌的浸润和转移密切相关。     

血管内皮生长因子在肾病大鼠中的表达及意义

目的:探讨血管内皮生长因子(VEGF)在阿霉素肾病大鼠中的表达及意义。方法:雄性Wistar大鼠62只,随机分为正常对照组、肾病综合征组(NS)。于7d、14d、28d检测血、尿、肾组织VEGF的含量。结果:N S组VEGF在血、尿、肾组织中的含量均显著高于正常对照组(P<0.01),且均与24h尿蛋白量呈正相关(r=0.775;0.807;0.629;P<0.01)。结论:阿霉素肾病大鼠血、尿、肾组织VEGF的表达与24h尿蛋白量呈正相关,提示VEGF参与了阿霉素肾病大鼠蛋白尿的发生。     

表皮生长因子受体及血管内皮生长因子在非小细胞肺癌组织中的表达

目的 观察非小细胞肺癌(NSCLC)组织中表皮生长因子受体(EGFR)和血管内皮生长因子(VEGF)的表达情况以及与临床病理特征的关系.方法 采用免疫组化法检测124例NSCLC组织和15例远离肿块无癌细胞浸润的肺组织(距肿瘤病变＞5 cm)标本EGFR、VEGF的表达.结果 EGFR、VEGF在124例NSCLC标本中的阳性表达率分别为52.4％、66.1％,在15例远离肿块无癌细胞浸润的肺组织(距肿瘤病变＞5 cm)均无表达.Ⅲ期NSCLC组织的VEGF表达率为80.4％ (41/51),高于Ⅰ-Ⅱ期的56.2％ (41/73)(x2=4.24,P＜0.05);淋巴结阳性的NSCLC组织VEGF表达率为78.2％ (50/64),明显高于淋巴结阴性的53.3％(32/60)(x2=4.77,P＜0.05),VEGF和EGFR表达与病理类型、性别、年龄、肿瘤细胞分化等无关.EGFR与VEGF呈正相关关系(r=0.93,P＜0.05).结论 EGFR、VEGF在NSCLC组织中过表达;VEGF可能与TNM分期及淋巴结转移有关,EGFR与VEGF在NSCLC肿瘤血管形成过程中可能起协同作用.