血管内皮抑素治疗恶性肿瘤的研究进展

重组人血管内皮抑素是一种广谱的抗血管生成分子靶向药物,其通过抑制肿瘤的病理性血管生成以及抑制肿瘤细胞的增殖和转移而发挥抗肿瘤作用.血管内皮抑素联合化疗已成为治疗各种恶性肿瘤的重要治疗手段.     

血管能抑素的应用及研究进展

血管能抑素是继血管生成抑制素、内皮抑素之后新发现的一种血管生成和肿瘤生长抑制因子。动物实验研究结果显示,血管能抑素通过抑制血管生成、阻断肿瘤生长的营养供应,从而抑制了多种肿瘤细胞的生长和转移。近年来因其具有良好的抗肿瘤血管生成活性而倍受关注,成为抗肿瘤治疗研究的新热点之一。本文就其作用机制尤其是在肿瘤治疗中的应用现状及研究进展进行综述和展望。     

血管内皮前体细胞和支气管肺癌的研究现状

肺癌是人类最常见的恶性肿瘤，但其发病隐匿，进展迅速，5年生存率仅15％。为了改善肺癌的生存率，肺癌的治疗从单一学科转化为多学科治疗。近年来，肿瘤分子生物学不断融人临床，分子靶向药物联合基础化疗的临床研究越来越广泛，在各种分子靶向药物中，较有治疗前途的是血管生成抑制剂类，包括贝伐单抗、血管内皮抑素等，它们主要靠抑制内皮细胞的有丝分裂来减少新生血管的形成，最终抑制肿瘤生长。ECOG4599的研究使贝伐单抗成为美国肺癌一线推荐治疗药物，而血管内皮抑素在国内的临床研究结果也令人鼓舞，但是如何评价这些药物对血管抑制的疗效以及是否有更好的靶点来抑制肿瘤血管，作为和肿瘤血管新生有密切联系的血管内皮前体细胞（endothelial progenitor cells，EPC，内皮祖细胞）成为肺癌新的研究方向。     

血管内皮抑素与肿瘤关系研究进展

 新生血管的生成在肿瘤的生长和转移中起重要作用,抗血管生成治疗已成为当今肿瘤治疗领域的热点,血管内皮抑素作为一种新型的内源性血管生成抑制剂,能特异性抑制内皮细胞的增殖和迁移,诱导细胞凋亡,并能抑制动物模型中新生血管生成,文章就内皮抑素的抗血管生成机制,诱导细胞凋亡及临床应用等方面进行综述。     

内皮抑素生物学特性及抗肿瘤作用的研究进展

概述了内皮抑素的起源、结构特征、作用机制及生物学功能 ,阐明了其对肺、胃、肝部等肿瘤的作用特征。内皮抑素的相对分子质量为 2 0× 10 3 ,是胶原蛋白 18C末端片断。内皮抑素抑制内皮细胞的增生 ,从而抑制血管生成 ,诱导内皮细胞凋亡。采用内皮抑素的抗血管生成疗法配合常规的外科手术、化疗、放疗和免疫疗法 ,必定会大大提高实体瘤的疗效。内皮抑素可成为新的重要的抗肿瘤药物 ,以其为主的综合治疗方案必将成为治疗肿瘤的新的有效方法     

内皮抑素的抗肿瘤作用展望

内皮抑素能够抑制内皮细胞的增生,对多种肿瘤的均有抑制作用,且无耐药性和毒性反应。锌对于内皮抑素的抗血管生成是必要的。内皮素的抗肿瘤机制在于它有一个肝素结合部位。内皮抑素必将成为肿瘤抗血管生成疗法的希望。     

血管内皮抑素在非小细胞肺癌治疗中的研究进展

肿瘤血管生成及其生长、侵袭和转移是一个复杂的多因素多步骤的调控过程。肿瘤生长及转移依赖于新生血管形成，抑制血管形成是抗肿瘤治疗的新方法。血管内皮抑素是一种新型内源性血管生成抑制剂，体内外试验证明其能特异性抑制血管内皮细胞的增殖与迁移，诱导其凋亡，从而抑制肿瘤新生血管的形成，达到抑制肿瘤生长的目的。有关血管内皮抑素的具体作用机制及信号传导通路尚不十分明确。同时其表达水平与肿瘤具有明显的相关性．可作为肿瘤的临床预后指标。血管内皮抑素的基因治疗与化疗、放疗、免疫治疗联合应用不仅显著增强其他治疗抗肿瘤效应，而且可减少其他治疗的毒副反应，显示出良好的临床应用前景。其抗血管生成作用具有广谱、低毒的特点，更重要的是克服了肿瘤的耐药性，这对于人类最终克服肿瘤是非常重要的。多年来国内外对其用于非小细胞肺癌治疗的报道较多。本文就血管内皮抑素的结构、作用机制、在非小细胞肺癌中的临床前及临床试验研究做一综述。     

重组人血管内皮抑素联合化疗治疗非小细胞肺癌的观察与护理

内皮抑素（endostatin,ES）为内源性抗血管生成因子,特异性地作用于内皮细胞,尤其是微血管的内皮细胞,抑制其迁移,诱导其凋亡,从而抑制血管生成和肿瘤生长,近年来已成为肿瘤治疗的新策略。2006年7月我国国家食品药品监督管理局正式批准重组人血管内皮抑制素（商品名：恩度）上市,成为世界上第一个血管内皮抑制素抗肿瘤新药。我院自2006年9月至今对36例非小细胞肺癌患者使用重组人血管内皮抑制素注射液联合化疗治疗,     

血管内皮抑素临床研究进展

抑制血管生成是治疗肿瘤的一种新策略,血管内皮抑素（ES）作为一种内源性血管生成抑制剂,在肿瘤治疗中有广阔的应用前景。其作用特点表现为特异性、广泛性和组织差异性。临床试验结果显示不易产生耐药性和无明显毒副作用的药理特征。针对单独给药疗效的不尽如意,与传统治疗方案联合协同增效达到治疗肿瘤的目的为其发展趋势之一,同时进一步改进药物形式降低成本和提高药物活性、稳定性及靶向性是另一研究方向。     

血管内皮抑素临床研究进展

抑制血管生成是治疗肿瘤的一种新策略,血管内皮抑素(ES)作为一种内源性血管生成抑制剂,在肿瘤治疗中有广阔的应用前景。其作用特点表现为特异性、广泛性和组织差异性。临床试验结果显示不易产生耐药性和无明显毒副作用的药理特征。针对单独给药疗效的不尽如意,与传统治疗方案联合协同增效达到治疗肿瘤的目的为其发展趋势之一,同时进一步改进药物形式降低成本和提高药物活性、稳定性及靶向性是另一研究方向。     

Mouse dendritic-endothelial cell hybrids and 4-1BB costimulation elicit antitumor effects mediated by broad antiangiogenic immunity

Antiangiogenic immunotherapy, which targets molecules critical to tumor angiogenesis, is expected to counteract the negative effect of tumor cell genetic instability on the outcome of immunotherapy targeting tumor antigens. Previously, targeting of individual angiogenic molecules has been shown to inhibit tumor angiogenesis and limit tumor growth. Nevertheless, this approach may be bypassed by redundant angiogenic pathways. To overcome this limitation, we have developed an immunization strategy targeting multiple molecules critical to angiogenesis. To this end, hybrids of dendritic cells (DC) and syngeneic endothelial cells (EC) were used as immunogens, because (a) whole EC express multiple molecules involved in angiogenesis and (b) DC tumor cell hybrids are effective in generating self-antigen-specific immune responses. The immunization strategy included the administration of an agonist 4-1BB-specific monoclonal antibody (mAb), because it augments self-antigen-specific immune responses elicited by DC hybrids. Immunization of mice with DC-EC hybrids and 4-1BB-specific mAb inhibited the growth of B16.F10 melanoma and MC38 colon adenocarcinoma tumors. This effect is mediated by EC-specific CD4+ and CD8+ T-cell responses, which markedly inhibited tumor angiogenesis. No therapy-related side effects, except minor and transient hematologic changes, were observed. Our findings represent a useful background for the design of antiangiogenic immunotherapeutic strategies to control tumor growth in a clinical setting.     

Lung cancer angiogenesis

Recent advances in our understanding of angiogenesis in solid tumor growth and metastasis has also led to intense investigation of angiogenesis and its clinical significance in lung cancer. This investigation has shown that angiogenesis is an important prognostic indicator for lung carcinoma and will become increasingly important when investigating new therapies aimed at inhibiting the formation of new blood vessels or targeting the tumor vasculature.     

沙利度胺治疗实体瘤的研究新进展

血管生成在实体瘤的生长、侵袭及转移方面发挥重要作用,以肿瘤血管生成的各个环节及其发生过程中的生化改变为靶点,研究血管生成抑制剂可以有效的抑制肿瘤生长、侵袭及复发。沙利度胺作为一种血管生成抑制剂,已经在治疗难治性多发性骨髓瘤方面取得良好的效果。本文简要综述其在实体瘤中应用的研究进展。     

Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma

Angiogenesis, the growth of new blood vessels from previously existing vasculature, is a requirement for tumor growth and metastasis. The first US FDA-approved drugs targeting angiogenesis have shown potential in the treatment of malignant gliomas. Immunotherapy as a treatment modality lends itself well to specifically targeting angiogenesis in tumors and may represent a powerful tool in the treatment of malignant gliomas. This review focuses on developments in immunotherapy targeting angiogenesis and tumor-vascular-specific endothelial cells using a variety of immunotherapeutic strategies including monoclonal antibodies and conjugated immunotoxins, as well as cellular, peptide, DNA and dendritic cell vaccines.     

A vaccine targeting basic fibroblast growth factor elicits a protective immune response against murine melanoma

Tumor growth and metastasis are closely related to angiogenesis. Basic fibroblast growth factor(bFGF) is an angiogenic factor, and up-regulated expression of bFGF plays a crucial role in the development and metastasis of melanoma. Therefore, in this study, we sought to achieve antitumor activity by immunity targeting bFGF which would inhibit tumor angiogenesis and simultaneously induce bFGF specific cytotoxic T lymphocytes to kill melanoma cells. A human bFGF protein was used as exogenous antigen, coupled with a saponin-liposome adjuvant formulation to enhance CTL response. The results showed that the immunity induced strong immune response and produced prominent anti-cancer activities. CD31 immunohistochemistry and alginate-encapsulated tumor cell assay displayed that tumor angiogenesis was effectively inhibited. Further, the higher production of IFN-γ and cytotoxic T lymphocyte killing assay suggested that the anti-cancer activities may mainly depend on cellular immune response, which could cause the inhibition of tumor angiogenesis and specific killing of tumor cells by bFGF-specific cytotoxic T lymphocytes. We concluded that immunotherapy targeting bFGF may be a prominent strategy for melanoma, and that the adjuvant formulation of saponin-liposome is very desirable in enhancing cytotoxic T lymphocytes response.     

Therapeutic efficacy of a synthetic epsin mimetic peptide in glioma tumor model: uncovering multiple mechanisms beyond the VEGF-associated tumor angiogenesis

Binding of epsin ubiquitin-interacting motif (UIM) with ubiquitylated VEGFR2 is a critical mechanism for epsin-dependent VEGFR2 endocytosis and physiological angiogenesis. Deletion of epsins in vessel endothelium produces uncontrolled tumor angiogenesis and retards tumor growth in animal models. The aim of this study is to test the therapeutic efficacy and targeting specificity of a chemically-synthesized peptide, UPI, which compete for epsin binding sites in VEGFR2 and potentially inhibits Epsin-VEGFR2 interaction in vivo, in an attempt to reproduce an epsin-deficient phenotype in tumor angiogenesis. Our data show that UPI treatment significantly inhibits and shrinks tumor growth in GL261 glioma tumor model. UPI peptide specifically targets VEGFR2 signaling pathway revealed by genetic and biochemical approaches. Furthermore, we demonstrated that UPI peptide treatment caused serious thrombosis in tumor vessels and damages tumor cells after a long-term UPI peptide administration. Besides, we revealed that UPI peptides were unexpectedly targeted cancer cells and induced apoptosis. We conclude that UPI peptide is a potent inhibitor to glioma tumor growth through specific targeting of VEGFR2 signaling in the tumor vasculature and cancer cells, which may offer a potentially novel treatment for cancer patients who are resistant to current anti-VEGF therapies.     

核素标记小分子多肽靶向诊治肿瘤新生血管的应用研究进展

早期诊断、精准治疗可以明显改善恶性肿瘤患者的预后。有研究发现肿瘤新生血管不仅在肿瘤的发生发展中起着极其关键的作用,也是肿瘤诊治的重要靶点。特定序列的多肽可以特异地靶向肿瘤新生血管内皮细胞上的特定分子。放射性核素标记这类小分子多肽所制备的分子探针在肿瘤诊治方面具有优势。本文将以我们的研究成果为主,阐述放射性核素标记小分子多肽RGD及RRL在靶向肿瘤新生血管的显像与治疗方面的应用研究进展。      

Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction.

Recent preclinical studies have suggested that radiotherapy in combination with antiangiogenic/vasculature targeting agents enhances the therapeutic ratio of ionizing radiation alone. Because radiotherapy is one of the most widely used treatments for cancer, it is important to understand how best to use these two modalities to aid in the design of rational patient protocols. The mechanisms of interaction between antiangiogenic/vasculature targeting agents and ionizing radiation are complex and involve interactions between the tumor stroma and vasculature and the tumor cells themselves. Vascular targeting agents are aimed specifically at the existing tumor vasculature. Antiangiogenic agents target angiogenesis or the new growth of tumor vessels. These agents can decrease overall tumor resistance to radiation by affecting both tumor cells and tumor vasculature, thereby breaking the codependent cycle of tumor growth and angiogenesis. The hypoxic microenvironment of the tumor also contributes to the mechanisms of interactions between antiangiogenic/vasculature targeting agents and ionizing radiation. Hypoxia stimulates up-regulation of angiogenic and tumor cell survival factors, giving rise to tumor proliferation, radioresistance, and angiogenesis. Preclinical evidence suggests that antiangiogenic agents reduce tumor hypoxia and provides a rationale for combining these agents with ionizing radiation. Optimal scheduling of combined treatment with these agents and ionizing radiation will ultimately depend on understanding how tumor oxygenation changes as tumors regress and regrow during exposure to these agents. This review article explores the complex interactions between antiangiogenic/vasculature targeting agents and radiation and offers insight into the mechanisms of interaction that may be responsible for improved tumor response to radiation.     

Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy

Vascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.     

It takes two to tango: Combinations of conventional cytotoxics with compounds targeting the vascular endothelial growth factor–vascular endothelial growth factor receptor pathway in patients with solid malignancies

Through advances in molecular biology, insight into the mechanisms driving malignancies has improved immensely and as a result, various factors playing an essential role in the biology of numerous tumor types have been revealed. By using compounds that specifically block the function of a single factor being crucial for tumor pathogenesis, it was hoped to exert antitumor activity while avoiding toxicities characteristic for conventional chemotherapy. One of the processes of crucial importance in the development of cancer, and consequently an attractive target, is angiogenesis. In recent years, several key factors for angiogenesis have been identified, including ligands, receptors, and transduction signaling factors. Of these, the vascular endothelial growth factor (VEGF) pathway has been found to be activated in numerous tumor types and considered one of the main drivers of angiogenesis. Roughly, VEGF-mediated angiogenesis can be inhibited by two approaches: either by monoclonal antibodies directed towards VEGF or its corresponding receptors, or by kinase inhibitors targeting the signal transduction of the VEGF receptors. As monotherapy, several kinase inhibitors exert antitumor activity in tumor types such as renal cell carcinoma. However, in most tumor types, the antitumor activity of compounds targeting the VEGF pathway is limited. In recent years, evidence is mounting that the paradigm of one single factor that drives malignant behavior applies rarely and is an oversimplification for most tumors in which there are multiple driving pathways. Consequently, multitargeting rather than single-targeting approaches are required. One of the means is by combining targeted agents with conventional cytotoxics. As the VEGF pathway also affects the sensitivity of tumor cells to chemotherapeutics, combinations of compounds targeting this pathway and conventional cytotoxics have been explored. This review addresses such combinations. ( Cancer Sci 2009; 00: 000–000)