靶向血管内皮生长因子/血管内皮生长因子受体-2的血管生成抑制剂

血管内皮生长因子(VEGF)及血管内皮生长因子受体-2(VEGFR-2)是调节血管生成、内皮细胞增殖和迁移等的关键调控因子。通过阻断VEGF与VEGFR-2的结合可抑制新生血管形成,而新生血管的形成是肿瘤生长和转移的基础。介绍VEGF/VEGFR-2在血管形成中的作用,以及具有抗肿瘤作用的靶向VEGF/VEGFR-2的血管生成抑制剂的研究近况。     

血管内皮生长因子及其受体在抗肿瘤治疗应用的研究进展

肿瘤的生长依赖肿瘤新生血管的形成。血管内皮生长因子（VEGF）是一类能促进血管生成的细胞因子，能诱导细胞的有丝分裂和调节内皮细胞的通透性。VEGF及其受体介导的肿瘤血管新生在肿瘤的生长和转移中具有重要的作用。本文综述了VEGF及其受体的分类、作用机制及在抗肿瘤治疗中的应用。     

VEGF165_b的抗血管生成作用在肾癌发生、发展中的研究进展

肾癌是一种高度血管化的恶性实性肿瘤,其生长和转移依赖于新生血管的形成,而血管形成主要是由促血管生成因子和抑制因子调控失衡、促血管生成因子增多所致。血管内皮生长因子(VEGF)亚型VEGF165是机体内含量最多,生物活性最强的促血管生成因子,且在肾癌组织中高表达,与肿瘤的生长、转移密切相关。最新研究发现一种新的VEGF异构体VEGF165b具有抑制VEGF165介导的血管生成作用,有可能成为肾癌治疗过程中新的作用靶点,具有重要的临床应用价值。本文对VEGF165b的结构、作用机制进行综述。     

血管内皮生长因子及其靶向治疗

血管新生在胚胎发育、器官形成、伤口愈合及其他正常生理过程中具有非常重要的作用.此外,在一些病理过程中也涉及血管生成,这些病理过程包括肿瘤的生长与转移、糖尿病引起的视网膜病变、年龄相关性黄斑变性、类风湿关节炎以及银屑病等.研究表明血管内皮生长因子(vascular endothelial growth factor,VEGF)在正常生理和病理性血管形成中起着非常重要的作用.因此,VEGF靶向治疗已成为肿瘤及相关疾病治疗的重要策略.     

靶向血管内皮生长因子及受体治疗肿瘤的研究进展

肿瘤的体积超过2～3mm~3时必须依赖新生血管的形成。血管生成(angiogenesis)是肿瘤生长转移的必须步骤,它是一个复杂的过程受多种促或抑血管生长因子的调控。其中血管内皮生长因子(vascular endothelial growth factor,VEGF)是已知作用最强,特异性最高的促血管生成因子。它是高度特异性的血管内皮细胞有丝分裂原,通过与血管内皮细胞特异性表达的受体Flt-1、Flk-1/KDR等结合,可显著增加血管通透性,刺激内皮细胞的增殖,直接诱导肿瘤新生血管的形成,从而为抗肿瘤提供了一种很有发展前途的治疗方法。现就抑制VEGF及其受体治疗肿瘤的研究现状作简要综述。     

舌癌组织中P53和血管内皮生长因子的表达及其与肿瘤血管形成的关系

<正>新生血管形成是肿瘤生长和转移的基础,血管内皮生长因子(VEGF)能刺激血管内皮细胞增殖,对肿瘤血管形成有重要作用。Mukhopadhyay等[1]和Fontanini等[2]认为,p53基因突变可通过调控VEGF的表达水平来影响肿瘤血管的形成。为了解突变型P53、VEGF和肿瘤内微血管密度     

VEGF受体酪氨酸激酶抑制剂的研究进展

肿瘤的生长和侵袭、转移依赖于新生血管的形成.抑制肿瘤介导的血管生成,阻断癌细胞的营养途径,就可有效抑制癌细胞增殖.血管内皮生长因子(VEGF)是肿瘤新生血管形成中的关键性促血管生长因子,它与特异性高表达在新生血管内皮细胞表面的受体酪氨酸激酶结合,激活酪氨酸激酶从而发挥生物学功能.因而以VEGF受体酪氨酸激酶为靶点的肿瘤血管靶向性治疗已成为近几年肿瘤治疗的新途径[1-3].     

妇科肿瘤与血管内皮生长因子关系的研究现状

新血管形成与肿瘤生长转移密切相关。血管生成是一种复杂的过程,包括内皮细胞激活、增生、迁移、血管基底膜破坏,形成新的血管和血管网,并与已存在的血管网连接。近年研究发现,有多种因子与肿瘤血管生成有关,其中血管内皮生长因子(vascular endothelial growth factor,VEGF)在血管形成过程中起重要作用,现就VEGF与妇科肿瘤关系作一综述。     

血管内皮细胞生长因子及其阻断在抗肿瘤中的应用

血管新生是实体瘤生长和转移的必要条件。血管内皮细胞生长因子(VEGF)及其受体在肿瘤血管新生中起重要作用，阻断VEGF的生成已成为抗肿瘤治疗的新靶点。     

VEGF与胃癌抗血管生成治疗进展

血管生成在恶性肿瘤的生长和转移中起着重要作用，且和患者的预后相关。研究发现新生血管的形成与肿瘤细胞分泌和激活的血管生长因子有关。血管内皮生长因子(vascular endothelid growth factor，VEGF）是一个重要的血管生长因子，在实体瘤的血管形成中起重要的作用。VEGF表达和胃癌的血管形成及转移密切相关，抗血管生成逐渐成为有效的胃癌预防和治疗的新靶点。本文阅读国内外有关文献进行简要综述。     

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.     

Inhibition of Tumor Growth and Metastasis by Targeting Tumor-Associated Angiogenesis with Antagonists to the Receptors of Vascular Endothelial Growth Factor

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 and pre-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 good 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. We have produced a panel of antibodies directed against the VEGF receptor 2, KDR/Flk-1. These antibodies potently block VEGF/KDR/Flk-1 interaction, and inhibit VEGF-stimulated activation of the receptor and proliferation of human endothelial cells. Further, the antibodies significantly inhibited tumor-associated angiogenesis in several animal models. Antagonists of VEGF and/or its receptors may offer higher specificity towards tumors with reduced side effects, and may be less likely to elicit drug resistance compared to conventional therapy. Anti-angiogenesis therapy represents a novel strategy for the treatment of cancer and other human disorders where pathological angiogenesis is involved.     

Vascular endothelial growth factor (VEGF) inhibition--a critical review

Angiogenesis, or formation of new blood capillaries from preexisting vessels, plays both beneficial and damaging roles in the organism. It is a result of a complex balance of positive and negative regulators, and vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors involved in tumor angiogenesis. VEGF increases vascular permeability, which might facilitate tumor dissemination via the circulation causing a greater delivery of oxygen and nutrients; it recruits circulating endothelial precursor cells, and acts as a survival factor for immature tumor blood vessels. The endotheliotropic activities of VEGF are mediated through the VEGF-specific tyrosine-kinase receptors: VEGFR-1, VEGFR-2 and VEGFR-3. VEGF and its receptors play a central role in tumor angiogenesis, and therefore the blockade of this pathway is a promising therapeutic strategy for inhibiting angiogenesis and tumor growth. A number of different strategies to inhibit VEGF signal transduction are in development and they include the development of humanized neutralizing anti-VEGF monoclonal antibodies, receptor antagonists, soluble receptors, antagonistic VEGF mutants, and inhibitors of VEGF receptor function. These agents can be divided in two broad classes, namely agents designed to target the VEGF activity and agents designed to target the surface receptor function. The main purpose of this review is to summarize all the available information regarding the importance of the pro-angiogenic factor VEGF in cancer therapy. After an overview of the VEGF family and their respective receptors, we shall focus our attention on the different VEGF-inhibitors existent nowadays. Agents based upon anti-VEGF therapy have provided solid proofs about their success, and therefore we believe that a critical review is of the utmost importance to help researchers in their future work.     

From proteins to nucleic acid-based drugs: the role of biotech in anti-VEGF therapy

Cancer cells, by releasing pro-angiogenic factors, stimulate the growth of the thick capillary net necessary for the nourishment of the tumor mass. The battle to defeat cancer uses today different approaches based on the inhibition of pathological angiogenesis: several compounds, either synthetic or biotech, aimed at this complex process, are under development. Vascular endothelial growth factor (VEGF) is considered the main target for an anti-cancer therapy based on angiogenesis inhibition; the goal is to block the interaction between this cytokine and its receptors in order to stop the intracellular signaling pathways leading to endothelium remodeling. FDA recently approved two drugs specifically aimed at VEGF, bevacizumab, a humanized monoclonal antibody, and pegaptinib, a pegylated aptamer with application in ophthalmic pathologies. These two approvals validate anti-VEGF therapy for clinical use, and show how biotech companies are investing on angiogenesis using different approaches, i.e. exploiting protein drugs and oligonucleotide-based therapeutics. Monoclonal antibodies, as well as other high molecular weight products like cytokine-traps, aptamers and short interfering RNA (siRNA), are designed to target VEGF and its receptors. Their design, production and clinical advancement in cancer and other pathological conditions linked to angiogenesis will be specifically addressed in this review.     

VEGF inhibitors in cancer therapy

Vascular endothelial growth factor (VEGF)-mediated angiogenesis is thought to play a critical role in tumor growth and metastasis. Consequently, anti-VEGF therapies are being actively investigated as potential anti-cancer treatments, either as alternatives or adjuncts to conventional chemo or radiation therapy. Among the techniques used to block the VEGF pathway are: 1) neutralizing monoclonal antibodies against VEGF or its receptor, 2) small molecule tyrosine kinase inhibitors of VEGF receptors, 3) soluble VEGF receptors which act as decoy receptors for VEGF, and 4) ribozymes which specifically target VEGF mRNA. Recent evidence from phase III clinical trials led to the approval of bevacizumab, an anti-VEGF monoclonal antibody, by the FDA as first line therapy in metastatic colorectal carcinoma in combination with other chemotherapeutic agents. However, may challenges still remain, and the role of anti-VEGF therapy in the treatment of other solid tumors remains to be elucidated. The aim of this article is to review the progress of clinical investigations involving VEGF inhibitors in the treatment of different types of solid tumors.     

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.     

Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy

Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have crucial roles in both physiological and pathological angiogenesis. The VEGF family consists of VEGF-A (generally called VEGF), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). These peptides show different affinities for VEGFR subtypes. VEGFR exists as three subtypes, VEGFR-1, VEGFR-2, and VEGFR-3, and is structurally related to platelet-derived growth factor receptors. All subtypes possess seven immunoglobulin-like domains in the extracellular region and a tyrosine kinase domain in the intracellular region. VEGF-A activates VEGFR-1 and VEGFR-2, whereas VEGF-B and PlGF bind to only VEFGR-1. VEGF-C and VEGF-D only bind to VEGFR-3. VEGFR-1 (fms-like tyrosine kinase-1, Flt-1) negatively regulates embryonic vasculogenesis and is involved in tumor angiogenesis via activation of monocytes and macrophages. VEGFR-2 (KDR in humans or Flk-1 in mice) is predominantly responsible for both embryonic vasculogenesis and tumor angiogenesis. In contrast, VEGFR-3 (Flt-4) regulates lymphangiogenesis. Consequently, VEGF-A and VEGFR-2 are currently the main targets for antiangiogenic therapy. Bevacizumab is a humanized monoclonal antibody against VEGF-A, and aflibercept (VEGF-Trap) is a soluble fusion protein of the extracelluar domain of VEGFR-1 and VEGFR-2 and the Fc region of immunoglobulin G (IgG). They neutralize VEGF-A, resulting in prevention of tumor angiogenesis. VEGFR tyrosine kinase inhibitors such as sunitinib and sorafenib are also effective in antiangiogenic tumor therapy by inhibiting VEGFR signaling. Anti-VEGF drugs are a promising therapy for cancer patients.     

Vascular endothelial growth factor as a survival factor in tumor-associated angiogenesis

This review focuses on vascular endothelial growth factors (VEGF), a group of structurally-related proteins that serve as key growth factors for tumor-associated angiogenesis. Pathways induced by VEGF proteins that regulate biological functions of key cell types involved in tumor angiogenesis, including vascular endothelial cells, pericytes and tumor cells, are discussed. Strategies that are currently being developed and tested based on the emerging definitions of the roles of the multiple cell types involved in tumor vessel development, their selective production of VEGF-related proteins and other pro-angiogenic growth factors, their expression of associated receptors as well as identification of signal transduction pathways involved in VEGF-induced tumor survival and tumor-associated angiogenesis will be reviewed.     

Characterization of a designed vascular endothelial growth factor receptor antagonist helical peptide with antiangiogenic activity in vivo

Angiogenesis is a fundamental process underlining physiological and pathological conditions. It is mainly regulated by the vascular endothelial growth factor (VEGF) and its receptors, which are the main targets of molecules able to modulate the angiogenic response. Pharmaceutical therapies based on antiangiogenic drugs represent a promising approach for the treatment of several socially important diseases. We report the biological and structural characterization of a VEGF receptor binder peptide designed on the N-terminal helix of VEGF. The reported experimental evidence shows that the peptide assumes in water a well-defined helical conformation and indicates that this peptide is a VEGF receptor antagonist and possesses antiangiogenic biological activity. In particular, it inhibits VEGF stimulated endothelial cell proliferation, activation, and survival, as well as angiogenesis and tumor progression in vivo. This peptide is a candidate for the development of novel peptide-based drugs for the treatment of diseases associated with excessive VEGF-dependent angiogenesis.