抗血管再生及抗血管内皮生长因子在肿瘤患者康复治疗中的研究

实体瘤的生成取决于肿瘤细胞团中血管的新生，肿瘤血管的新生受到众多血管刺激及抑制因子的调控。血管内皮生长因子被认为是其中最重要的血管生长刺激因子，它高度特异地与血管内皮细胞的Flt-1和KDR受体结合，直接参与肿瘤血管的生成并激发其他血管生长刺激因子的作用。随着肿瘤血管再生理论和相应基础临床研究的快速进展，抗肿瘤血管生成治疗已成为肿瘤综合治疗中的一项重要内容。人工已能提取血管抑素等血管生长抑制激素用于临床治疗研究。一些传统的抗血管生成药物也因此开辟了新的研究应用领域。作为肿瘤血管生长的最重要刺激因子，抗血管内皮生长因子的方法和药物研究也在紧张的进行，并取得了卓越的进展。就血管生成在肿瘤发生发展中的作用、肿瘤治疗研究中的意义、抗肿瘤血管生成以及抗内皮生长因子研究中的进展进行综述。     

肿瘤抗血管治疗的研究进展

实体肿瘤的生成依赖于肿瘤本身新生血管的形成,肿瘤血管的再生受到众多血管刺激及抑制因子的调控。随着肿瘤血管再生理论和相应基础临床研究的快速进展,抗肿瘤血管生成治疗已成为肿瘤综合治疗中的一项重要内容。目前,已有多种血管生长抑制因子如血管抑素、肿瘤抑素等用于临床治疗研究,一些传统的抗血管生成药物也因此开辟了新的研究应用领域。现对血管生成（angiogenesis）在肿瘤发生发展中的作用、肿瘤治疗研究中的意义、抗肿瘤血管生成基因治疗研究中的进展作一综述。     

内皮抑素及其抑制肿瘤血管新生的机制

研究开发针对肿瘤血管生成的抗肿瘤药物是限制肿瘤生长和防止其转移的有效策略 ,内皮抑素是迄今疗效较好的血管生成抑制剂。关于内皮抑素抑制肿瘤血管生成的机制主要有以下几个方面 :干扰血管生成因子作用 ;抑制血管内皮细胞增殖和 (或 )诱导其凋亡 ;阻断内皮细胞表面粘附因子作用。通过抑制肿瘤新生血管生成 ,达到治疗肿瘤的目的     

内皮抑素及其抑制肿瘤血管新生的机制

研究开发针对肿瘤血管生成的抗肿瘤药物是限制肿瘤生长和防止其转移的有效策略，内皮抑素是迄今疗效较好的血管生成抑制剂。关于内皮抑素抑制肿瘤血管生成的机制主要有以下几个方面：干扰血管生成因子作用；抑制血管内皮细胞增殖和(或)诱导其凋亡；阻断内皮细胞表面粘附因子作用。通过抑制肿瘤新生血管生成，达到治疗肿瘤的目的。     

血管内皮生长因子受体与恶性肿瘤

肿瘤的生长和转移依赖于新生血管的形成 ,已知有多种细胞因子、生长因子及其受体参与了血管形成的调控 ,其中血管内皮生长因子 (VEGF)可能是最关键的刺激因子。而VEGF的生物学效应是通过其特异性的膜受体介导实现的 ,迄今发现VEGF有三种受体 :VEGFR 1、VEGFR 2、VEGFR 3。它们在血管生成中的调节作用和以VEGFR为靶点的抗肿瘤治疗研究 ,是当前研究的热点。本文主要综述这方面的进展     

肿瘤血管生成抑制因子tumstatin的研究进展

肿瘤的生长和转移都依赖于新生血管的生成,通过抑制血管生成而切断肿瘤营养供给的方法一直是肿瘤生物治疗的研究热点。内源性新生血管抑制剂靶向性治疗肿瘤具有不产生耐药性、无毒副作用以及广谱性,故应用前景良好。肿瘤抑素(tumstatin)是最新发现的来源于基底膜Ⅳ型胶原的肿瘤血管生成的内源性抑制因子。本文就tumstatin在肿瘤生长、转移中的作用,及在肿瘤诊断研究中的意义、抗肿瘤血管生成基因治疗研究中的进展进行综述。     

血管内皮生长因子受体与恶性肿瘤

肿瘤的生长和转移依赖于新生血管的形成，已知有多种细胞因子、生长因子及其受体参与了血管形成的调控，其中血管内皮生长因子(VEGF)可能是最关键的刺激因子。而VEGF的生物学效应是通过其特异性的膜受体介导实现的，迄今发现VEGF有三种受体：VEGFR—1、VEGFR—2、VEGFR—3。它们在血管生成中的调节作用和以VEGFR为靶点的抗肿瘤治疗研究，是当前研究的热点。本文主要综述这方面的进展。     

小分子抗血管生成药物在晚期乳腺癌中的研究进展

截至2020年，乳腺癌已取代肺癌，成为全球第一大癌，而晚期乳腺癌的预后却极不理想。尽管目前仍以化疗为主要的治疗方法，但由于它的不良反应较强，且容易出现抗药性，使其临床获益受限。新生血管生成在肿瘤的发展和转移中起着关键作用，因此抗血管生成治疗成为肿瘤研究的热点领域。VEGFR是一种重要的血管内皮生长因子，它能够促进血管的生长，但是它在乳腺癌等多种肿瘤中过量表达。因此，通过抑制VEGFR的活性，可以有效地抑制肿瘤的血管生长并使肿瘤血管正常化。目前已经开展了许多小分子抗血管生成药物在乳腺癌治疗中的临床研究。本文旨在探究VEGFR酪氨酸激酶抑制剂（VEGFR-TKIs）作为一种有效的晚期乳腺癌患者的治疗方法，以及它们的效用、安全性和潜在的不良反应。另一方面，也为晚期乳腺癌的姑息治疗提供新的思路。     

抗肿瘤血管治疗的耐药性

血管生成(angiogenesis)是指单个成血干细胞或内皮细胞从已形成的微血管网以出芽方式延伸,经重组改建形成更成熟的血管包括动脉、静脉和毛细血管的过程。1971年,Folkman首先提出肿瘤生长依赖于血管生成,抑制肿瘤新生血管将成为抑制肿瘤生长新策略,为肿瘤的治疗开辟了新的思路[1]。抗肿瘤血管疗法主要包括抗血管生成和靶向作用于血管两种[2]。有时,同一药物兼有两种作用,难于明确区分。能够破坏或者抑制肿瘤的新生血管生成、有效地阻止肿瘤生长和转移的药物称为肿瘤新生血管生成抑制剂,其机制如下:①抑制基底膜降解:代表性药物为MMP抑制剂M…     

人血管内皮生长因子在肿瘤广谱筛查和临床诊断中的应用

肿瘤的生长和转移依赖于新血管的生成（Angiogenesis）,而肿瘤新血管的生成是在肿瘤血管生成刺激因子和抑制因子的共同调控下进行的。血管内皮生长因子（Vascular endothelial growth factor,VEGF）是肿瘤血管新生中最重要的刺激因子,也是目前研究最多和最广泛的课题。1994年,Kondo等人首次报道了癌症病人血清VEGF水平高于正常对照,从而开始了VEGF血液（包括血清和血浆）含量与肿瘤的发生、发展、以及治疗过程中VEGF的变化的实验性临床研究,并获得了大量的研究资料。本文收集了国内外关于“血液VEGF与肿瘤诊断”研究论文500余篇,英文文献279篇,中文文献236篇。     

New strategies in anti-vascular cancer therapy

Angiogenesis is a critical step in the progression of tumours from dormancy to a clinical relevant cancer. Inhibition of this process is one of the most promising new anti-cancer strategies. To develop new drugs that interfere with the cascade of events required for the formation of new blood vessels, insight into this process is essential. Here, we discuss the molecular basis of angiogenesis and the concepts of vascular targeting. Furthermore new strategies will be discussed to discover surface markers on endothelial cells that confer sufficient specificity for targeted intervention in the tumour vasculature.     

Detection of anti-vascular endothelial cell antibodies with microcytotoxicity testing

Antivascular endothelial cell antibodies (anti-VEC) were detected in 20 out of 20 serum samples from post renal transplant nephrectomy patients using a microcytotoxicity (MET) test, but in only 1 of 100 healthy blood donors. Cytotoxicity to VEC could occur in the absence of lymphocytotoxic antibodies. In this paper factors influencing the specificity and sensitivity of microcytotoxicity on vascular endothelial cell (VEC) were studied, including improvements in the preparation of VEC from an umbilical cord vein to get 95% and more of purity and viability; adequate dilution of rabbit sera to reduce its nonspecific VEC cytotoxic effect; and results read by exactly adjusted phase contrast microscopy to reduce the percentage of false negative. The original titers of allotypic and monoclonal antibodies against VEC have been shown to be reproducible in repeated testing during the past two years. The recognition of the weak cytotoxic effects of anti-HLA on VEC makes possible direct application of microcytotoxicity on VEC, to detect anti-VEC and to study VEC antigen classification (through a comparison of the cytotoxic effects of tested sera on VEC and concordant lymphocytes).     

晚期非小细胞肺癌抗血管生成治疗

上世纪的Meta分析结果证实化疗可比最佳支持治疗带来更多临床受益,故其一直为晚期非小细胞肺癌(NSCLC)的主导治疗.但一线化疗有效率仅25%～35%、1年生存率仅30%～45%.     

抗血管内皮生长因子治疗糖尿病性黄斑水肿对视网膜外层结构恢复的效果

目的 探讨玻璃体腔注射雷珠单抗(intravitreal ranibizumab, IVR)治疗糖尿病性黄斑水肿(diabetic macular edema, DME)过程中对视网膜外层结构完整性的恢复效果。方法 回顾性观察我院24例(28眼)已确诊DME患者,所有患眼行玻璃体腔注射雷珠单抗0.05 ml,平均随访时间(8.21±1.56)个月。详细记录所有患眼治疗前后最佳矫正视力(BCVA),并换算为最小分辨角对数(logMAR)视力;SD-OCT仪分析所有患者治疗过程中黄斑区特征,包括黄斑中心凹视网膜厚度(central macular thickness, CMT)、视网膜外界膜(external limiting membrane, ELM)及光感受器椭圆体带(ellipsoid zone, EZ)完整性的变化。结果 28眼基线平均logMAR视力为1.38±0.21,首次注射后6个月的平均logMAR视力为0.39±0.08,治疗前后差异有统计学意义(P<0.05)。基线平均CMT为(416.36±23.10)μm,首次注射后6个月的平均CMT为(231.15±38....     

Intravitreal steroid and anti-vascular endothelial growth agents for the management of retinal vein occlusion: evidence from randomized trials

Introduction: Retinal vein occlusion (RVO) is a common retinal vascular disorder, affecting visual acuity and quality of life. Macular edema (ME) and retinal ischemia are the main causes for visual impairment in RVO. Although several modalities have been evaluated for the treatment of ME secondary to RVO in clinical trials, various questions need to be clarified when translating clinical trials into real-world practice.

Areas covered: Intravitreal steroids and anti-VEGF agents are now widely used for the treatment of ME due to RVO. Herein, evidence from randomized controlled trials regarding the use of steroids and anti-VEGF agents in ME related to RVO are presented. In addition, an approach regarding the optimal treatment regimen, the most suitable time for initiating treatment and monitoring patients, as well as the potential role of ischemia in the response to treatment and the impact of treatment on the natural course of the disease was made.

Expert opinion: A comprehensive presentation of randomized clinical trials evaluating intravitreal steroids and anti-VEGF treatment for RVO indicates that both are effective and safe. However, the comparative effectiveness of the various anti-VEGF agents, the most suitable dosing regimen and the effect of these agents on retinal ischemia remains unclear.     

Treatment of experimental breast cancer using interleukin-12 gene therapy combined with anti-vascular endothelial growth factor receptor-2 antibody

We have shown previously that interleukin-12 (IL-12) gene therapy induced strong antitumor effects in several syngeneic murine tumor models including 4T1 mammary adenocarcinoma. Antiangiogenic treatment with a monoclonal antibody (mAb) directed against the vascular endothelial growth factor receptor-2 (VEGFR-2) is another promising treatment approach that can cause transient suppression of tumor growth. We hypothesized that the combination of IL-12 gene therapy and anti-VEGFR-2 mAb will achieve better antitumor and antimetastatic effects against 4T1 adenocarcinoma than each treatment alone via implementation of different mechanisms. Administration of anti-VEGFR-2 mAb into BALB/c mice bearing s.c. 4T1 tumors induced significant suppression of tumor growth, as did intratumoral administration of naked IL-12 DNA. The combined treatment with anti-VEGFR-2 mAb and IL-12 DNA resulted in significantly enhanced inhibition of tumor growth as compared with each treatment alone. This combination was also effective against spontaneous lung metastases. In T-cell-deficient nude mice, both IL-12 DNA and anti-VEGFR-2 mAb were effective in suppressing tumor growth. In T-cell- and natural killer cell-deficient scid/beige mice, only anti-VEGFR-2 mAb was effective, suggesting that natural killer cells are involved in the antitumor effects induced by IL-12 DNA. In both types of immunodeficient mice, the combination of anti-VEGFR-2 mAb and IL-12 DNA was as effective in suppressing 4T1 tumor growth as anti-VEGFR-2 mAb alone. Antitumor effects of anti-VEGFR-2 mAb were associated with the inhibition of angiogenesis within the tumors, whereas the antiangiogenic effect of IL-12 gene therapy was not detected. Our results show a therapeutic benefit of combining IL-12 gene therapy and anti-VEGFR-2 mAb for cancer treatment.     

抗血管内皮生长因子药物在新生血管性青光眼手术中的应用效果及对患者预后的影响

目的探究抗血管内皮生长因子(VEGF)药物在新生血管性青光眼手术中的应用效果及对患者预后的影响。方法选取我院2018年1月至2019年3月收治的93例新生血管性青光眼患者为研究对象,采用随机数字表法将其分为常规组(46例,引流器植入术)和干预组(47例,雷珠单抗+引流器植入术)。比较两组患者的临床疗效。结果治疗后,两组的VEGF水平均降低,且干预组明显低于常规组(P<0.05)。治疗后,两组的眼压均降低,视力均升高,且干预组的眼压及视力均明显优于常规组(P<0.05)。随访结束后,干预组的功能性滤过泡生成率明显高于常规组(P<0.05)。结论新生血管性青光眼患者引流器植入术前在玻璃体腔内注射雷珠单抗,不仅可有效降低患者房水中VEGF水平,还有助于降低患者的眼压,改善患者的视力,促进功能性滤过泡的生成,效果显著,预后较佳,值得在临床上推广应用。     

Genetic delivery of the murine equivalent of bevacizumab (avastin), an anti-vascular endothelial growth factor monoclonal antibody, to suppress growth of human tumors in immunodeficient mice

Vascular endothelial growth factor (VEGF) produced by tumor cells plays a central role in stimulating angiogenesis required for solid tumor growth. VEGF-specific antibodies inhibit tumor cell line growth in animal models and a humanized monoclonal anti-VEGF antibody (bevacizumab [Avastin]) is approved as a treatment for metastatic cancer. We hypothesized that administration of an adenoviral (Ad) vector expressing the murine monoclonal antibody equivalent of bevacizumab would suppress human tumor growth in vivo. The Ad vector (AdalphaVEGF) encodes the light chain and heavy chain cDNAs of monoclonal antibody A.4.6.1, a murine antibody that specifically recognizes human VEGF with the same antigen-binding site as bevacizumab. AdalphaVEGF efficacy in vivo was evaluated with A-673 rhabdomyosarcoma and DU 145 prostate carcinoma cells in human tumor cell xenografts in SCID mice. For both tumor models, AdalphaVEGF directed the expression of high anti-human VEGF IgG antibody titers in vivo, the numbers of mitotic nuclei and blood vessels in the tumor were significantly decreased (p < 0.05), tumor growth was suppressed (p < 0.05), and there was increased survival (p < 0.005). Thus, AdalphaVEGF, encoding a murine monoclonal antibody that is the equivalent of bevacizumab, effectively suppresses the growth of human tumors, suggesting gene therapy as an alternative to bevacizumab monoclonal antibody therapy.