肿瘤血管生成机制及抗肿瘤血管新生的靶向药物研究进展

抗肿瘤血管新生治疗是以血管内皮细胞为靶点,通过降低血管活性因子的活性、抑制内皮细胞增殖和迁移、改变肿瘤生长微环境,从而抑制肿瘤生长过程中的血管新生,切断肿瘤的供养,最终达到遏制肿瘤生长和转移的目的,是一种全新的靶向肿瘤治疗方法.该方法具有高效特异性、不易产生耐药性、药物易于到达靶部位和毒副作用小等优点,可以有效地抑制肿瘤的转移和复发,现在已成为抗肿瘤血管生成药物研究的热点之一,该文综述了肿瘤血管生成的机制及抗血管新生治疗药物的最新研究进展.     

肿瘤新血管生成抑制剂的研究进展

肿瘤新血管生成(angiogenesis)是原发性肿瘤赖以发生、生长和转移的物质基础[1],它在肿瘤的新陈代谢和转移过程中起着关键性的作用。若能破坏和抑制肿瘤新血管的生成,切断肿瘤生长和转移所依赖的“命脉”,就可能阻止肿瘤的生长和转移,这就使肿瘤的血管生成系统成为肿瘤药物治疗的新靶点。由于肿瘤新血管生成具有较强的特异性,血管内皮细胞暴露于血液中,以及血管内皮细胞的基因表达相对稳定等特点,这对于直接靶向作用于肿瘤血管内皮细胞的肿瘤新血管生成抑制剂就具有疗效高、特异性强、剂量小、不易产生耐药性和毒副作用低等优点。随着人们对…     

肿瘤血管内皮是肿瘤导向给药与免疫疗法的屏障或者靶区

采用化疗，药物靶向制剂及免疫调节剂直接攻击肿瘤细胞治疗实体肿瘤的方法，由于受肿瘤脉管系统的屏障作用，难以取得满意的疗效，在肿瘤血管内皮细胞，基底膜或肿瘤基质中，可能存在一些潜在的肿瘤特异性靶向给药部位，近年来出现了导向这些靶部位的新型给药方法。这些方法通过增加肿瘤血管通透性，可以提高药物在肿瘤中的蓄积；通过抑制肿瘤血管生成并切断肿瘤供血，可以阻止肿瘤生长；通过调节肿瘤内皮细胞粘附分子的表达，可以诱     

整合素αvβ3拮抗剂的研究进展

肿瘤生长初期没有新血管生成（无血管期）,其生长到一定程度时依赖新生血管的维持.肿瘤血管生成是肿瘤生长和转移的形态学基础,它不仅向肿瘤提供营养,也向宿主输出大量的肿瘤细胞导致肿瘤的生长和转移.因此对以抑制肿瘤血管生成为目的的抗肿瘤药物的研究方兴未艾,有很多具有抑制肿瘤血管生成作用的化合物如大黄素与青蒿琥酯等被发现.整合素αvβ3介导血管内皮细胞和肿瘤细胞的黏附,参与血管生成和肿瘤转移,在肿瘤生长中起重要作用.当其功能受到抑制时,血管内皮细胞出现凋亡,肿瘤生长受到抑制,甚至肿瘤消退.整合素αvβ3受体拮抗剂作为抗新生血管肿瘤药物的同时,对骨质流失、血栓、风湿性关节炎的治疗也起了重要作用.     

中药抗肿瘤血管生成研究述略

血管生成是实体瘤生长、浸润和转移的一个重要因素，因此肿瘤血管生成已成为抗肿瘤治疗的新靶点。与传统的肿瘤治疗相比，抗肿瘤血管生成药物主要针对已经启动的新生血管，故具有特异性。而且血管内皮细胞暴露于血流中，药物能直接发挥作用，故有剂量小、疗效高、一般不造成骨髓抑制、胃     

新的血管生成抑制肽抗肿瘤血管生成的实验研究

目的观察一种新的血管生成抑制肽对肿瘤的抑制作用，并初步探讨作用机制。方法体外药效实验，采用MTT法及血管内皮细胞迁移法，体内采用Lewis肺癌瘤株皮下接种C57BL／6N小鼠，兔眼角膜烧伤模型。观察血管生成情况。结果新的血管生成抑制肽对血管内皮细胞增殖、迁移有明显的抑制作用。体内使Lewis肺癌皮下移植瘤体积明显缩小，并对烧伤诱导的兔眼角膜新生血管也具有明显抑制作用。结论新的血管生成抑制肽能明显抑制Lewis的肿瘤生长，其机制可能与抑制肿瘤血管生成有关。     

内皮抑素概论及抗肺癌作用

肿瘤的生长转移与肿瘤血管生成密切相关,抗血管生成是治疗肿瘤的新策略.内皮抑素是特异性的血管内皮细胞生长抑制因子,能显著抑制肿瘤血管增生并诱导肿瘤细胞凋亡.内皮抑素的抗血管生成治疗和血管靶向基因治疗,为治疗肺癌提供了广阔前景 .     

作用于VEGF信号通路的血管生成抑制剂

分类介绍作用于血管内皮细胞生长因子信号通路的血管生成抑制剂研究近况以及该类药物存在的缺陷。血管生长促进因子和血管抑制因子的活性及其表达水平对肿瘤的发生和发展具有关键性的作用,所以,针对于血管生成,尤其是靶向于血管内皮细胞生长因子的药物已成为近年来抗肿瘤药物研究的热点之一。     

治疗晚期肾癌的新靶向药物阿西替尼

Folkman于1970年首次提出了肿瘤血管生成理论,并认为肿瘤的生长和转移都依赖于新生血管的形成[1]。研究发现众多的促血管生成因子和抑制因子在肿瘤血管生成过程中起调控作用,血管内皮生长因子(VEGF)是其中很重要的一类。VEGF是血管生成的主要调控因子,可特异性地作用于血管内皮细胞,在体外及体内都是内皮细胞增殖和迁移的强烈刺激因素,对肿瘤血管的形成具有重要的意义,是实体瘤生长和进展过程中重要的调节因     

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。     

The effect of linomide on the migration and the proliferation of capillary endothelial cells elicited by vascular endothelial growth factor.

In order to assess the mechanism of action of the quinoline-3-carboxyamide linomide as an antiangiogenic drug, the effect of linomide was studied in vitro on postcapillary endothelial cells exposed to vascular endothelial growth factor (VEGF). Linomide did not block the spontaneous replication of endothelial cells, but significantly suppressed endothelial cell growth and migration elicited by VEGF. It is concluded that linomide appears to be an effective tool to inhibit VEGF-dependent angiogenesis.     

Bradykinin antagonists as new drugs for prostate cancer

Bradykinin (BK) is an autocrine growth factor for lung and prostate cancers. BK also facilitates tumor extension by increasing tissue permeability and stimulating angiogenesis. Peptide BK antagonists are in development as potential new drugs for lung cancer. Newer nonpeptide BK antagonists have even higher potency against lung cancer, in vitro and in vivo. These compounds have now been applied to the study of prostate cancers, and have been found to be effective. Prostate cancer cell line PC3 is derived from a late-stage, hormone-independent, metastatic tumor; its growth is difficult to inhibit. Our established BK antagonists, while less effective against this line of prostate cancer in xenografts in nude mice than against lung cancer, are active and have led the way to development of new peptide and nonpeptide agents for prostate cancer. In addition to inhibiting cancer cell growth directly, they inhibit angiogenesis mediated by vascular endothelial growth factor, and inhibit increased tissue permeability mediated by membrane metalloproteases in these tumors. This class of compounds offers hope for development of new drugs for refractory prostate cancer.     

Angiogenesis and its inhibition: potential new therapies in oncology and non-neoplastic diseases.

To summarise the key points: The ability to mount an angiogenic response is probably present in all tissues, and stimulation of endothelial cells by any one of a wide variety of factors initiates a cascade of events leading to angiogenesis. In most tissues the overall lack of angiogenesis in normal situations probably results from the interaction of a complex series of multifactorial systems, each of which maintained in a state of balance between stimulation and inhibition. An imbalance in any one of these systems, for example by an increase in the concentration of a growth factor, may lead to angiogenesis. Inhibition of angiogenic stimuli is unlikely to be effective as an approach to new angiostatic drugs, given the multiple stimulatory pathways available. Tumour cells for example may induce angiogenesis via release of numerous growth factors, prostaglandins etc, and by their attraction of inflammatory cells which in turn release multiple angiogenic stimuli. Inhibitory modulation of many of the individual steps of capillary growth which occur following an angiogenic stimulus can block the angiogenic response. This leads to the expectation that an effective inhibitor of a single key step in this cascade would be able to completely suppress angiogenesis. Inappropriate angiogenesis is an important factor in many diseases including cancer and arthritis. In particular angiogenesis is an absolute requirement for neoplastic growth of solid tumours, and the establishment of secondary growths. There is also a strong link between induction of angiogenesis by a tumour and its ability to metastasise. Several drugs with proven clinical effects in diseases involving angiogenesis have recently been found to be angiogenesis inhibitors, and this may be their primary mechanism of action. In particular the activities of methotrexate and gold compounds in arthritis, and alpha-interferon and medroxyprogesterone in cancer therapy may be due to inhibition of angiogenesis. In animal models, treatment with angiogenesis inhibitors has proven anti-tumour effects in vivo, and can both reduce metastases and lead to regression of the primary growth by necrosis following capillary retraction. In man the success of alpha-interferon and TNF alpha in AIDS related Kaposi's sarcoma may be due to inhibition of angiogenesis. Interferon has also been successfully used to treat pulmonary hemangiomatosis, in which angiogenesis in the lung may be the pathogenic basis of the disease.     

Antiangiogenic drugs: current knowledge and new approaches to cancer therapy

Angiogenesis--process of new blood-vessel growth from existing vasculature--is an integral part of both normal developmental processes and numerous pathologies such as cancer, ischemic diseases and chronic inflammation. Angiogenesis plays a crucial role facilitating tumour growth and the metastatic process, and it is the result of a dynamic balance between proangiogenic and antiangiogenic factors. The potential to block tumour growth and metastases by angiogenesis inhibition represents an intriguing approach to the cancer treatment. Angiogenesis continues to be a topic of major scientific interest; and there are currently more antiangiogenic drugs in cancer clinical trials than those that fit into any other mechanistic category. Based on preclinical studies, researchers believe that targeting the blood vessels which support tumour growth could help treatment of a broad range of cancers. Angiogenic factors or their receptors, endothelial cell proliferation, matrix metalloproteinases or endothelial cell adhesion, are the main targets of an increasing number of clinical trials approved to test the tolerance and therapeutic efficacy of antiangiogenic agents. Unfortunately, contrary to initial expectations, it has been described that antiangiogenic treatment can cause different toxicities in cancer patients. The purpose of this article is to provide an overview of current attempts to inhibit tumour angiogenesis for cancer therapy.     

Angiogenesis inhibitors in cancer therapy

The formation of new blood vessels is essential for tumor growth and progression. Angiogenesis inhibitors have been demonstrated to block tumor growth and/or metastasis. Although initial clinical data have been disappointing, new strategies to increase the efficacy of these drugs have ensured their ongoing clinical development. This review highlights the broad spectrum of angiogenesis inhibitors under investigation in both preclinical and clinical studies. From 'natural' inhibitors to thalidomide analogs, the number of compounds in development is extensive. Elucidating the mechanisms of action will enable their use in conjunction with existing/other novel therapies, thereby maximizing the potential efficacy of angiogenesis inhibitors to fulfill their promise in patients with cancer.     

免疫检查点抑制剂与抗血管生成药物合用治疗肿瘤的研究进展

免疫检查点抑制剂(immune checkpoint inhibitor,ICI)通过阻断免疫负调节信号激活机体的抗肿瘤免疫应答,临床试验表明,ICI仅对部分晚期癌症患者有效。而通过阻断肿瘤血管生成常用的抗血管生成药物尽管可以抑制肿瘤的生长,对患者的生存期却未体现出改善,且存在耐药等应用局限。肿瘤免疫反应与血管生成密切相关,同时,肿瘤血管生成高度依赖于免疫抑制微环境。近来一些研究表明,ICI联合血管生成抑制剂不但可以减轻其治疗耐药性,且疗效优于任何单一疗法。联合疗法加强血管正常化和免疫重编程之间的正反馈循环,调节肿瘤免疫微环境以诱导机体持久的抗肿瘤免疫反应。该文对ICI联合抗血管生成疗法的最新进展展开论述,以期为后续研究提供新的思路与借鉴。     

Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target

To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.     

Comparison of kinetic properties of quinidine and dofetilide block of HERG channels

Many drugs inhibit human ether-a-go-go related gene (HERG) current and prolong cardiac action potential duration. We examined the kinetic properties of quinidine block of HERG channels expressed in Xenopus oocytes in comparison with those of the block by a class III antiarrhythmic dofetilide. Both of the drugs inhibited HERG currents in a use-dependent and frequency-independent manner. However, the underlying mechanisms were different. Under the steady state, quinidine block was voltage- and time-dependent. At positive membrane potentials, the onset of block was very fast. Thus, quinidine caused frequency-independent block mainly through this fast blocking kinetic. In contrast, dofetilide blocked HERG currents in a voltage- and time-independent manner under the steady state because of very slow unblocking at negative potentials, which also caused frequency-independent block. Therefore, quinidine and dofetilide might cause the reverse frequency-dependent prolongation of action potential duration through distinct mechanisms with regard to blocking and unblocking kinetics.     

麦考酚酸对flk-GFP斑马鱼模型抗血管生成的作用机制研究

目的从已上市药物中筛选出具有抑制血管生成作用的小分子化合物麦考酚酸(免疫抑制剂)并对其抗血管生成作用机制进行研究。方法用flk-GFP转基因斑马鱼作为观察血管生成的动物模型,从含有大部分已上市药物的1120种化合物库(Prestwick Chemical,Inc.)中,筛选出具有典型抑制血管生成的药物麦考酚酸(MPA);对其抑制血管生成的作用进行量效分析,通过目标基因敲出技术和微注射方法,研究flk-GFP转基因斑马鱼胚胎注射次黄嘌呤核苷磷酸脱氢酶(IMPDH)的吗啉反义寡核苷酸(MO)3种亚型的血管生成抑制作用。结果麦考酚酸抑制血管生成的作用与药物浓度成正相关,且有明显的血管生成阻断作用,提示IMPDH2 MO能显著抑制斑马鱼的血管生成(n>200,表型比例>50%)。结论麦考酚酸通过抑制IMPDH2从而产生血管生成抑制作用。