内皮抑素在肺癌治疗中的应用

1971年Folkman首次发现肿瘤的生长依赖于血管生成,肿瘤细胞通过血管获得生长所需营养,血管为肿瘤转移提供通道,从此抗血管生成为肿瘤的治疗的领域。1997年O’Reilly等首先发现内皮抑素（endostatin）能特异地抑制内皮细胞增殖和迁移,进而可以抑制新生血管的生成,这为抑制肿瘤的侵袭、转移找到了新的思路。多年来,国内外学者开展的许多有关内皮抑素的基础和临床研究都表明其具有独特的抗肿瘤活性。现将近年来内皮抑素在肺癌治疗中的应用综述如下。     

姜黄素联合内皮抑素对小鼠肉瘤生长抑制及血管生成的影响

目的探讨姜黄素与内皮抑素联合治疗对小鼠皮下移植肉瘤的生长抑制以及血管生成的影响。方法随机将72只荷瘤小鼠分为对照组、姜黄素组、内皮抑素组和联合治疗组,分别给予相应药物治疗,每天l次,连续给药14d,观察肿瘤生长情况,在荷瘤小鼠处死前从小鼠的尾静脉注射荧光标记物后分离肿瘤组织,计算抑瘤率,观察肿瘤灌注血管荧光标记,计算肿瘤组织的灌注血管平均距离及微血管密度。结果各药物治疗组对肿瘤的生长都有明显的抑制作用,姜黄素组、内皮抑素组、联合治疗组的抑瘤率分别为30.93%,32.33%,61.66%;对照组、姜黄素组、内皮抑素组及联合治疗组的平均灌注血管距离分别为(35.29±6.45),(56.42±9.57),(59.15±10.06),(76.98±11.16)μm,微血管密度分别为(60.35±11.22),(45.23±8.76),(44.77±8.03),(29.62±5.81)个·(400Hp)-1,各药物治疗组与对照组比较差异有统计学意义(P<0.05),联合治疗组与单独用药组比较具有明显的统计学差异(P<0.01);单独用药组之间相比差异无统计学意义。结论姜黄素与内皮抑素治疗小鼠皮下移植肉瘤时都能够抑制肿瘤血管的生成,降低微血管密度,抑制肿瘤的生长,且二者联合治疗的作用效果更佳,明显优于单独用药治疗,表明二者对实体肿瘤的抗血管生成治疗具有协同作用。     

肿瘤血管生成抑制剂

恶性肿瘤的发展与侵袭均依赖于新生血管生成。肿瘤新生血管的生成受多种调节因子作用,这些调控因子主要有：血管内皮生长因子、血管生成素,成纤维细胞生长因子,血管抑素,内皮抑素,thrombospondin(TSP-1)等。通过抑制肿瘤新生血管的生成可以阻止肿瘤的发展和转移,甚至使肿瘤消退。抗血管生成药物为肿瘤的治疗提供了一个全新的思路,本文简单讨论了肿瘤血管生成与调节机制并着重介绍肿瘤血管生成抑制剂的研究进展。     

抑制肿瘤血管生成疗法的研究进展

简要回顾抗血管生成疗法在肿瘤治疗中的重要成果,着重概括抑制血管生成的四主要环节:中和血管形成促进物、使用血管形成抑制物、调节血管抑素和内皮抑素、靶向肿瘤内皮细胞,并列举了部分进入临床试用的抗血管药。在综述既往研究成果的基础上,提出抗肿瘤血管疗法的未来展望。     

肿瘤血管生成及其供血模式研究进展

在肿瘤的生长、侵袭和转移过程中,肿瘤血管生成研究尤为重要。本文对目前研究较多的肿瘤血管生成过程、相关影响因子及不同供血模式等方面做…综述。研究表明肿瘤生长分为无血管的缓慢生长阶段和血管快速增长阶段。在无血管的缓慢生长阶段,促血管生成因子（如血管内皮细胞生长因子VEGF、成纤维细胞生长因子FGF、整合素INT等）和血管生成抑制因子（如内皮抑素Es、血管抑素AS、血小板反应蛋白-1TSP-1等）处于平衡状态,当实体肿瘤达到或超过1-2mm2时,单纯依靠弥散作用已不能满足自身营养需求,肿瘤自身缺血缺氧诱导促血管生成因子产生,平衡状态被打破,血管生成表型启动。在肿瘤的生长过程中,各种因子相互作用,肿瘤组织内部会出现不同的供血模式,主要有血管生成拟态VM、马赛克血管MV和内皮依赖性血管三种。VM完全以肿瘤细胞变形构建：MV由不连续内皮细胞和肿瘤细胞相间构建;内皮依赖性血管完全由内皮细胞衬覆。有文献将此三种模式称为“三阶段现象”即肿瘤供血模式由Ⅷ到MV再到内皮依赖性血管。目前,抗血管生成在肿瘤治疗研究中占据重要的地位,但还有许多问题尚未清晰。我们更需进一步研究,为抗血管生成在临床上的应用及与传统抗肿瘤治疗方法的结合提供充实的理论依据。     

canstatin抗肿瘤作用研究现状

肿瘤的生长及转移均依赖于血管新生。抗血管生成治疗已成为肿瘤的治疗热点,目前以内源性血管生成抑制因子研究为主。血管能抑素（canstatin）是新近发现的一种来源于IV型胶原蛋白的内源性抗血管新生抑制因子,具有较强的抗血管新生作用而受到重视,现综述其抗肿瘤研究现状。     

内皮抑素临床研究新进展

早在20世纪初,Goldman就观察到血管围绕肿瘤生成现象。1971年,Judah Folkman博士提出“肿瘤生长和转移依赖血管生成,阻断血管生成是遏制肿瘤生长的有效策略”,即所谓的肿瘤饥饿疗法。其中,1997年发现的内皮抑素(Endostatin)[1]因抑制血管生成作用强而备受关注。本文就内皮抑素临床应用的最新进展作一综述。1生物学特性及作用机制1·1起源和结构特征1997年,O'Reilly MS等[1]发现,可从体外培养的小鼠血管内皮细胞瘤(EOMA)的细胞培养液中提纯出内皮抑素,且与人的内皮抑素同源性极高。经氨基酸序列分析表明,二者大约有86%完全一致,仅人的内…     

血管生成抑制因子抗肿瘤作用的研究进展

病理性血管生成是肿瘤生长和转移的关键步骤之一,因而阻断或抑制新血管生成是抗肿瘤的有效策略[1]。近年来人们对肿瘤血管的形成机制进行了广泛研究,已证明血管的生成受多种促进和抑制因子的调节,相继有多种促血管生成分子和抗血管生成分子被分离鉴定[2]。以血管生成为靶点治疗肿瘤已成为肿瘤治疗研究的热点,有多种血管生成抑制剂已进入临床试验阶段。本文对几种很有应用前景的血管生成抑制因子的研究现状作一综述。EndostatinEndostatin即血管内皮抑素,是1997年在鼠内皮细胞瘤细胞培养液中提取并命名的一种蛋白。它由胶原ⅩⅧC末端区内18…     

抗肿瘤新生血管药物治疗进展

新生血管是肿瘤赖以生长和生存的物质基础,肿瘤细胞需要新生血管提供营养物质和排出废物。新生血管的生长和成熟是一个复杂的多因子和多信号传导过程的结果,其中涉及到很多血管生成因子,如血管内皮生长因子(VEGF),血管生成素和抑制血管生成的因子(如内皮细胞抑制素,肿瘤抑素,可     

重组人血管内皮抑素联合放化疗治疗宫颈癌的疗效分析

<正>近年来,抗血管生成已成为治疗肿瘤侵袭和转移的一个新的研究领域。相关研究表明[1],内皮抑素在肿瘤血管生成中的诸多环节中发挥着重要作用,可间接导致肿瘤细胞休眠或退缩。重组人血管内皮抑素(Endostar,商品名:恩度)是我国在内皮抑素的基础上,自主研发的新型抗血管形成的抗肿瘤靶向治疗药物。大量研究表明~[2,3],对肺癌、结肠癌、胃癌、肝癌等多种肿瘤均有明显疗效,美国国立综合癌症网络(NCCN)、     

肿瘤血管生成机制及抗血管生成药物的研究进展

目的：介绍肿瘤血管生成的机制及其抑制剂的研究进展.方法：查阅国内外相关文献进行总结和归纳.结果：肿瘤血管生成的机制目前发现的有5类：芽生式、套叠式、充塞式、内皮祖细胞的参与、马赛克式及血管生成拟态.目前有一批FDA批准上市的血管生成抑制剂（如贝伐单抗、sunitinib malate和sorafenib等）已用于肿瘤的治疗,还有更多的药物正在研究之中.结论：研究肿瘤血管生成的机制对进一步研究肿瘤血管生成抑制剂有着重要的指导作用.     

Hypoxia control to normalize pathologic angiogenesis: potential role for endothelial precursor cells and miRNAs regulation

Tumor microenvironment is a complex and highly dynamic milieu that provides very important clues on tumor development and progression mechanisms. Tumor-associated endothelial cells play a key role in stroma organization. They achieve tumor angiogenesis, a formation of tumor-associated (angiogenic) vessels mainly through sprouting from locally preexisting vessels and/or recruitment of bone marrow-derived endothelial progenitor cells. This process participates to supply nutritional support and oxygen to the growing tumor. Endothelial cells constitute the interface between circulating blood cells, tumor cells and the extracellular matrix, thereby controlling leukocyte recruitment, tumor cell behavior and metastasis formation. Hypoxia, a critical parameter of the tumor microenvironment, controls endothelial/tumor cell interactions and is the key to tumor angiogenesis development. Under hypoxic stress, tumor cells produce factors that promote angiogenesis, vasculogenesis, tumor cell motility, metastasis and cancer stem cell selection. Targeting tumor vessels is a therapeutic strategy that has lately been fast evolving from antiangiogenesis to vessel normalization as discussed in this review. We shall focus on the pivotal role of endothelial cells within the tumor microenvironment, the specific features and the part played by circulating endothelial precursors cells. Attention is stressed on their recruitment to the tumor site and their role in tumor angiogenesis where they are submitted to miRNAs-mediated de/regulation. Here the compensation of the tumor deregulated angiogenic miRNAs - angiomiRs - is emphasized as a potential therapeutic approach. The strategy is to over express anti-angiomiRs in the tumor angiogenesis site upon selective delivery by precursor endothelial cells as miRs carriers.     

抗肿瘤血管生成抑制剂TNP-470的研究进展

肿瘤是一种血管生成依赖性疾病,肿瘤的生成、转移均与血管生成密切相关.烟曲霉素合成类似物TNP-470能有效抑制肿瘤血管生成,破坏血管内皮细胞增殖,从而抑制肿瘤的生成与扩散.当前TNP-470正处于治疗各种肿瘤的临床试验中.本文就近几年来,对TNP-470的研究进展作一综述.     

大豆异黄酮抑制裸鼠移植瘤生长及其血管生成的实验研究

目的　探讨大豆异黄酮及其主要有效成分金雀黄素对人乳腺癌细胞裸鼠移植瘤的生长及其血管生成的影响。方法　选用人乳腺癌细胞株MCF 7裸鼠异种移植 ,观测移植瘤的重量、出瘤时间、成瘤率 ,同时应用FⅧ免疫组化染色 ,观测瘤组织内的新生血管。结果　FⅧ免疫组化染色结果表明 ,肿瘤组织内可见形态不规则 ,且无明显管腔的新生血管 ,血管分布以肿瘤组织的边缘处为多见。各组微血管记数结果金雀黄素组最少。肿瘤出瘤时间及成瘤率各防治组都明显延长和减少 ,以金雀黄素组最为明显 ,其次是高黄酮组和低黄酮组。结论　大豆异黄酮的主要有效成分金雀黄素能减少肿瘤的血管生成 ,从而抑制裸鼠移植瘤的体内生长。     

国产创新药安罗替尼抗肿瘤治疗的研究进展

血管新生是恶性肿瘤细胞增殖、生长、转移过程中的重要环节,抗肿瘤血管新生药物在肿瘤治疗中起重要作用。安罗替尼是我国自主研发的多靶点小分子酪氨酸激酶抑制剂,其主要作用于血管内皮生长因子受体(VEGFR)-1、VEGFR-2、VEGFR-3、血小板衍生生长因子受体、成纤维细胞生长因子受体、c-Kit、Ret等多个靶点,可以阻断肿瘤血管生成并抑制肿瘤生长。多项临床试验证实安罗替尼在非小细胞肺癌、软组织肉瘤、小细胞肺癌、甲状腺髓样癌、肾癌和结直肠癌中均具有良好的疗效和安全性。     

Crosstalk between cancer cells and endothelial cells: implications for tumor progression and intervention

Communication between tumor cells and stromal cells is crucial to tumor development and progression. Fibroblasts and macrophages are the most common stromal cells in the tumor microenvironment. Endothelial cells are another type of stromal cell in the tumor microenvironment required for angiogenesis via interaction with tumor cells. Tumor angiogenesis provides not only oxygen and nutrients for tumor cells but also the necessary anchorage to facilitate tumor metastasis. The present review summarizes studies on the crosstalk between cancer cells and endothelial cells with a focus on implications for tumor progression. The following four categories are discussed in this review: (1) cell–cell communication in tumor microenvironment; (2) induction of metastasis by interaction between cancer cells and endothelial cells; (3) angiogenesis induced by tumor cells; (4) therapeutic strategies targeting adhesion and signaling molecules as well as chemokines. This review provides useful information highlighting the process of cancer aggressiveness affected by the crosstalk between cancer cells and endothelial cells, and suggests therapeutic strategies against tumor progression.     

Markers of tumor angiogenesis: clinical applications in prognosis and anti-angiogenic therapy

Numerous studies in many tumor types have demonstrated that quantitation by microvessel as a measure of angiogenesis is a powerful prognostic tool. However, the ability to exploit tumor angiogenesis as a prognostic marker is limited by the methods currently used for capillary identification and quantitation. This report critically evaluates all aspects of the techniques and their associated problems used for assessing tumor angiogenesis in tissue sections including the area of tumor assessed, the vascular parameter measured, the method of quantitation, the stratification of patients and the practical utility of computer image analysis systems. The potential of angiogenic factors assays, proteolytic enzymes, and cell adhesion molecules as surrogate endpoints for quantifying tumor angiogenesis are discussed and other methods for quantifying tumor angiogenesis are described. The potential clinical applications of these angiogenic markers in prognosis, stratification for adjuvant treatments (both cytotoxic and anti-angiogenic/vascular targeting) and other aspects of patient management is also discussed, particularly design of phase I and II trials.     

他汀类药物抗肿瘤作用机制的研究进展

他汀类药物属于3-羟基-3-甲基戊二酸单酰辅酶A还原酶抑制剂,近年来大量的临床研究显示,他汀类药物也具备抗肿瘤作用。他汀类药物可以通过抑制肿瘤细胞增殖、促进肿瘤细胞凋亡、抑制肿瘤细胞侵袭和迁移、抗肿瘤血管生成、增强抗肿瘤免疫等发挥抗肿瘤作用。因此总结了他汀类药物的抗肿瘤作用机制,期望为他汀类药物进一步应用于肿瘤的治疗提供科学依据和理论支撑。     

Combination therapy of cRGD-DOX self-assembled nanoparticles and bevacizumab for breast cancer

The interplay among diverse cell populations in the tumor microenvironment contributes to tumor progression. Targeting to different cell populations might result in improved therapeutic effects on malignant tumors. Integrins high express on many kinds of tumor cells, and VEGF has a strong effect on tumor angiogenesis. Therefore, based on tumor cells and angiogenesis, we fabricated integrin-targeting cRGD-DOX nanoparticles and combined them with the anti-VEGF antibody bevacizumab. We evaluated the antitumor effect of this combination therapy in an integrin-overexpressing MDA-MB-231 tumor model. The cRGD-DOX nanoparticles were effectively uptake by MDA-MB-231 cells and the uptake was related to the expression of integrinin; cRGD-DOX nanoparticles showed less cytotoxic than free DOX; Bevacizumab did not show significant cytotoxicity against MDA-MB-231 cells at concentrations less than 1 mg/mL. The in vivo results showed that bevacizumab could reduce tumor interstitial fluid pressure; the combination of bevacizumab and cRGD-DOX nanoparticles showed enhanced antitumor effects compared with the corresponding single-agent treatments. These findings suggested the combination of angiogenesis antibody and integrin-targeting nanoparticle loaded with a cytotoxic drug was a promising cancer treatment regimen.     

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.