贝伐单抗在恶性脑胶质瘤中应用

恶性脑胶质瘤细胞的生长依赖于肿瘤血管生成,血管内皮生长因子（VEGF）是其有效治疗靶点。贝伐单抗可选择性结合VEGF,抑制肿瘤血管形成,从而达到抗肿瘤目的。全文就贝伐单抗在恶性脑胶质瘤中的应用情况作一介绍。     

贝伐珠单抗治疗非小细胞肺癌脑转移的研究进展

脑部是肺癌最常见的远处器官转移部位之一,肺癌脑转移的发生率高,是脑转移性肿瘤中最常见的类型,同时也是肺癌死亡率居高不下的原因之一。抗肿瘤血管生成治疗已成为肺癌治疗的重要手段之一,抗血管生成药物贝伐珠单抗也成为继全脑放疗、立体定位放疗和化疗之后肺癌脑转移患者新的治疗选择。目前,对脑转移的非小细胞肺癌患者应用贝伐珠单抗治疗的临床研究也越来越多,其安全性和有效性是研究重点。本文就贝伐珠单抗治疗非小细胞肺癌脑转移的研究进展做一综述。     

培美曲塞维持治疗恶性胸膜间皮瘤患者的疗效和安全性分析

背景 与目的恶性胸膜间皮瘤(malignant pleural mesothelioma,MPM)是原发于胸膜且恶性程度高的一类肿瘤.晚期胸膜间皮瘤预后差,中位生存时间不超过15个月.一线标准化疗方案推荐是含培美曲塞的双药联合,加或不加贝伐珠单抗.目前一线标准化疗有效的患者能否从培美曲塞维持化疗中获益,尚无统一结论.本...     

贝伐珠单抗所致蛋白尿的研究进展

贝伐珠单抗作为血管内皮细胞生长因子(VEGF)信号通路的阻断药之一,可通过影响VEGF信号通路,抑制肿瘤新生血管的生成,从而达到抑制肿瘤生长的目的。近年来,贝伐珠单抗已被广泛应用于肿瘤的抗血管生成的治疗中,尤其是其在转移性结直肠癌、非小细胞肺癌、转移性肾细胞癌等肿瘤的治疗中疗效显著。不同于使用传统细胞毒性化疗药物产生的不良反应,使用VEGF信号通路阻断药会出现蛋白尿、高血压、出血等不良反应,而贝伐珠单抗的临床应用在很大程度上又受到蛋白尿这一不良反应的限制,不仅降低了整体的临床获益,也不利于患者的治疗及预后。使用贝伐珠单抗进行治疗是否会导致蛋白尿的发生,与患者的用药剂量、用药疗程、肿瘤类型、是否合并使用肾毒性药物、是否具有肾脏相关基础性疾病等多种因素有关。目前,对于使用贝伐珠单抗导致蛋白尿,其发生机制尚不十分明确,且无针对性的预防和治疗手段。本文就使用贝伐珠单抗而产生蛋白尿的发生原因、可能机制、影响因素和治疗方案等作一综述。     

贝伐珠单抗在恶性脑水肿治疗中的应用

以贝伐珠单抗为主的抗血管生成药物通过减少血管通透性和血脑屏障破坏,能有效减轻恶性脑水肿,缓解临床症状,改善患者生命质量。贝伐珠单抗在治疗恶性脑水肿方面取得了积极的疗效,因此被认为是治疗恶性脑水肿的一种安全、有效的治疗手段。     

恶性胸腔积液治疗进展

恶性胸腔积液(malignant pleural effusion,MPE)指原发于胸膜或其他部位的恶性肿瘤转移至胸膜引起的胸腔积液。几乎所有恶性肿瘤发展到晚期都会出现MPE,其中以肺癌、乳腺癌最常见,病理类型以腺癌最多见[1]。MPE的出现表明肿瘤播散或已进展至晚期,随着胸腔积液量的增加,患者生活质量会明显下降,预期寿命将显著缩短,中位生存期为4~9个月[2],虽然治疗MPE的方法较多,但治疗效果有限。目前MPE     

胃肠道肿瘤的抗血管生成治疗

抗血管生成是治疗肿瘤的新途径。血管内皮生长因子(VEGF)是目前已知作用最强的促血管形成因子,因而是抗血管生成治疗的主要靶点。本文重点综述贝伐单抗等几种抗血管生成药物治疗结直肠癌的研究进展,并简要叙述消化道其他肿瘤抗VEGF研究的情况。     

抗肿瘤血管生成:肺癌治疗新希望——2006年ASCO新进展

近年来抗肿瘤血管生成治疗逐渐成为肺癌靶向治疗的热点。前不久刚结束的2006年ASCO大会公布了贝伐单抗及小分子血管内皮生长因子受体(VEGFR)酪氨酸激酶抑制剂(TKI)的研究新进展,其结果令人鼓舞。VEGF是一种细胞因子,它能诱导内皮细胞增生、蛋白酶的表达、抗内皮细胞凋亡和细胞重组,最终形成毛细血管。在病理血管生成方面,它还能增强血管的通透性,形成不成熟的血管网络。血管上皮生长因子能够刺激血管内皮细胞的增生,在大多数人体肿瘤组织中(包括肺癌),VEGF的表达大大高于其他正常组织[1]。研究证实贝伐单抗以VEGF作为靶点,具有一…     

VEGF和VEGFR通路抑制剂在晚期胃癌治疗中的疗效

抗新生血管形成是目前胃癌治疗的重要研究方向,血管内皮生长因子(VEGF)及血管内皮生长因子受体(VEGFR)抑制剂是主要的研究热点.目前治疗晚期胃癌的VEGF及VEGFR通路抑制剂包括贝伐珠单抗、雷莫芦单抗、阿帕替尼、瑞戈非尼、索拉非尼等,这些药物为晚期胃癌的治疗提供了更多可能性.     

贝伐单抗治疗晚期大肠癌的研究进展

血管内皮生长因子(VEGF)是目前已知作用最强的促血管形成因子,因而是抗血管生成治疗的主要靶点.贝伐单抗是抗VEGF受体的人源单克隆抗体,可抑制肿瘤血管生成,目前用于一线治疗大肠癌.     

Prognostic Values of VEGF and Endostatin with Malignant Pleural Effusions in Patients with Lung Cancer

Aims: Angiogenesis is important in malignant pleural effusion (MPE) formation and it is regulated by anumber of pro- and anti-angiogenic cytokines. The purpose of this study was to evaluate the prognostic valueof angiogenic factor vascular endothelial growth factor (VEGF) and angiogenesis inhibitor endostatin in lungcancer patients with MPE, and investigate the relationship between these two kinds of agent. Methods: Usingenzyme-linked immunoadsorbent assay, the concentrations of VEGF and endostatin were measured in pleuraleffusions (PE) and serum from a total of 70 lung cancer patients with MPE and 20 patients with tuberculosis.Results: Compared to patients with tuberculosis, the levels of VEGF and endostatin in both PE and serum weresignificantly higher in patients with lung cancer. There were statistically significant correlations between VEGFlevels in PE and serum (r=0.696, p<0.001), endostatin levels in PE and serum (r=0.310, p=0.022), and VEGF andendostatin levels in PE (r=0.287, p=0.019). Cox multivariate analysis revealed that elevated pleural VEGF andendostatin levels and serum endostatin level were independent predictors of shorter overall survival. Conclusion:Both pro- and anti-angiogenic factors are likely contributors to PE formation. Our results suggest that the levelsof VEGF and endostatin in PE, together with endostatin in serum, may be potential prognostic parameters forlung cancer patients with MPE.     

Closing faucets: the role of anti-angiogenic therapies in malignant pleural diseases

Malignant pleural effusion (MPE) represents 15–35 % of pleural effusions and markedly worsens the prognosis and quality of life of patients with cancer. Malignant mesothelioma (MM) and lung adenocarcinoma are the most frequent primary and secondary causes, respectively, of MPE. Effective treatments for cancer-related MPE are warranted in order to improve symptoms, reduce the number of invasive pleural procedures, and prolong patient life. Since angiogenesis plays a key role in MPE development, the potential role of bevacizumab and other anti-angiogenic therapies have been explored in this review. No relevant phase III trials have specifically analysed the benefit from adding bevacizumab to platinum-based chemotherapy in lung cancer-related MPE. However, small retrospective series reported 71.4–93.3 % MPE control rate, a reduction in invasive procedures, and a safe profile with this combination. Being approved for the first-line treatment of non-squamous advanced NSCLC, the addition of bevacizumab should be considered for patients presenting with MPE. In addition, further studies in this are recommended. In MM, the addition of bevacizumab to platinum-based chemotherapy did not meet primary endpoints in two phase II trials. However, the beneficial results on OS reported in comparison with historical cohorts and the statistically significant benefit on PFS and OS observed in the phase III MAPS trial foretell an eventual role for the combination of platinum/pemetrexed/bevacizumab as front-line systemic therapy for pleural MM. To date, no other anti-angiogenic drug has showed significant benefit in the treatment of patients with either MPE or MM. However, new promising drugs such as ramucirumab or recombinant human endostar warrant further investigation.     

水通道蛋白1及其mRNA在胸膜恶性肿瘤进展中的作用

目的 探讨胸膜恶性肿瘤的进展对水通道蛋白1（aquaporin-1,AQP1）及其mRNA的影响。方法 通过胸膜腔注射法建立胸膜恶性肿瘤的动物模型,按肿瘤种植时间分组（T6,T8,T10）,记录各组胸水量,采用免疫组织化学法、Real-Time PCR的方法测定AQP1及AQP1-mRNA水平。结果 肿瘤小鼠胸水量随时间而增长;壁层胸膜AQP1及其mRNA水平随肿瘤进展而增高,且与胸水量呈正相关。结论 在胸膜恶性肿瘤的进展中,胸膜壁层AQP1及其mRNA水平升高,胸水量与AQP1、AQP1-mRNA水平呈正相关,进而提示AQP1参与了胸膜恶性肿瘤的构建和进展。     

Tumor necrosis factor-alpha promotes malignant pleural effusion

Tumor necrosis factor (TNF)-alpha is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF-alpha in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor- and host-derived TNF-alpha were assessed using combined experimentation with TNF-alpha gene-deficient mice and in vivo TNF-alpha neutralization. To expand the scope of preclinical data, TNF-alpha and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF-alpha of host and tumor origin was present. TNF-alpha neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF-alpha and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF-alpha gene-sufficient and TNF-alpha gene-deficient mice. In mouse cancer cells, TNF-alpha functioned via nuclear factor-kappaB- and neutral sphingomyelinase-dependent pathways to induce TNF-alpha and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF-alpha and VEGF content of human MPE. We conclude that tumor-derived TNF-alpha is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF-alpha blockade against malignant pleural disease.     

Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor prognosis, therefore development of novel effective therapies is urgent. In the present study, we investigated the therapeutic efficacy of vandetanib (ZD6474), an inhibitor of VEGFR-2, EGFR and RET tyrosine kinases, in an orthotopic model of MPM. We found that a human MPM cell line, EHMES-10, expressed RET/PTC3 oncogenic rearrangement and a large amount of VEGF. Vandetanib induced the apoptosis and inhibited the proliferation of EHMES-10 cells in vitro (IC(50)=0.3 microM). Once-daily oral treatment with vandetanib inhibited tumor angiogenesis, and reduced significantly the growth of thoracic tumors and the production of pleural effusions, resulting in the prolonged survival of mice in EHMES-10 orthograft model. In contrast, the selective EGFR tyrosine kinase inhibitor, gefitinib, had no effect against EHMES-10 cells both in vitro and in vivo. Our results suggest that using vandetanib to target RET-dependent tumor cell proliferation and survival and VEGFR-2-dependent tumor angiogenesis may be promising against MPM expressing RET oncogenic rearrangement and VEGF.     

Vascular endothelial growth factor promoter‐based conditionally replicative adenoviruses effectively suppress growth of malignant pleural mesothelioma

Malignant mesothelioma (MM) incidence is increasing drastically worldwide as an occupational disease resulting from asbestos exposure. However, no curative treatment for MM of advanced stage is available. Thus, new therapeutic approaches for MM are required. Because malignant pleural mesothelioma (MPM) cells spread along the pleural surface in most patients, MPM can be targeted using intrapleural therapeutic approaches. In this study, we investigated the effectiveness of the intrapleural instillation of a replication‐competent adenovirus as an oncolytic agent against MPM. We constructed a vascular endothelial growth factor promoter‐based conditionally replicative adenovirus (VEGF‐CRAd) that replicates exclusively in VEGF‐expressing cells. All of the MM cell lines that we tested expressed VEGF mRNA, and VEGF‐CRAd selectively replicated in these MM cells and exerted a direct concentration‐dependent oncolytic effect in vitro. Furthermore, our in vivo studies showed that pre‐infection of MM cells with VEGF‐CRAd potently suppressed MPM tumor formation in nude mice, and that intrapleural instillation of VEGF‐CRAd prolonged the survival time of tumor‐bearing mice. Our results indicate that VEGF‐CRAd exerts an oncolytic effect on MM cells and that intrapleural instillation of VEGF‐CRAd is safe and might represent a promising therapeutic strategy for MPM.     

A sulindac analogue is effective against malignant pleural effusion in mice

Objectives

To examine whether a sulindac derivative (C-18) with previously reported anti-angiogenic properties limits malignant pleural effusion (MPE) formation in mice.

Methods

MPE was generated by intrapleural injection of murine adenocarcinoma cells in C57BL/6 mice. Animals were divided into three groups, a control group and two treatment groups receiving intraperitoneally a daily dose of either 1 mg or 2 mg of C-18 for a total of 12 doses. Mice were sacrificed on day 14.

Measurements and main results

Pleural fluid volume and the number of pleural tumor implantations were measured. Tumor angiogenesis, pleural vascular permeability and the host inflammatory response were also assessed. C-18 significantly limited pleural fluid formation and inhibited intrapleural tumor dissemination. The mean ± SEM pleural fluid volume was 758 ± 63 μl for the control group, compared to 492 ± 120 μl (p = 0.042) and 279 ± 77 μl (p < 0.001) for the low dose and high dose group of C-18, respectively. Control group animals had 6.2 ± 1 intrapleural tumors, while C-18 treated animals had 3.1 ± 0.8 (p = 0.014) and 3 ± 0.7 (p = 0.009) for the low and high dose respectively. In addition C-18 significantly suppressed pleural vascular permeability. No significant difference in tumor angiogenesis and inflammatory response was observed, while there was also no measurable effect in tumor cell apoptosis and proliferation in vitro and in vivo.

Conclusions

C-18 halted experimental MPE formation and intrapleural tumor dissemination, through down-regulation of pleural vascular permeability.     

Osteopontin is involved in the formation of malignant pleural effusion in lung cancer

Malignant pleural effusion (MPE) is associated with advanced-stage lung cancer and is a poor prognostic sign for these patients. Osteopontin (OPN) is a multifunctional cytokine that is involved in the tumor progression and angiogenesis of lung cancer cells. The purpose of this study is to investigate and provide evidence for the role of OPN in the formation of MPE associated with lung cancer. In this study, we established an OPN knockdown murine lung cancer cell line, 3LL cells, utilizing the small interfering RNA (siRNA) technique. To reveal the effect of OPN on the formation of MPE associated with lung cancer, we directly injected OPN knockdown 3LL cells, 3LL/OPN siRNA, or control cells, 3LL/control siRNA, into the pleural space of C57BL/6 mice. OPN knockdown significantly reduced the formation of MPE, but did not inhibit in vivo tumor growth of 3LL cells in mice. Vascular endothelial growth factor (VEGF) concentration in MPE was markedly decreased in the 3LL/OPN siRNA in comparison with that of the 3LL/control siRNA. In vitro, recombinant OPN protein enhanced VEGF secretion from human umbilical vein endothelial cell (HUVEC) or human mesothelial cell line, Met5A cells, in a concentration-dependent manner. These results suggest that OPN is positively involved in the formation of MPE of lung cancer presumably by promoting VEGF secretion from vascular endothelial cells or mesothelial cells. OPN could be an effective target molecule for reducing MPE in lung cancer patients.     

恶性胸膜间皮瘤45例临床分析

背景与目的恶性胸膜间皮瘤是一种罕见疾病,其发病率在逐年上升,早期诊断和治疗非常困难。本文旨在探讨恶性胸膜间皮瘤的临床特点、诊断及治疗,为临床提供参考。方法回顾性分析解放军总医院1997年1月-2010年12月收治的45例恶性胸膜间皮瘤患者的临床资料。结果恶性胸膜间皮瘤患者的主要临床症状为胸痛(53.33%)、胸闷气促(48.89%)和咳嗽(37.78%);CT表现主要为胸膜增厚(71.11%)、胸腔积液(60%)和肺部阴影(40%);胸水以渗出液为主,有核细胞数明显增多,以单核细胞的增多为主,乳酸脱氢酶明显增高;大部分患者临床分期为Ⅲ期和Ⅳ期;确诊的方式主要是胸腔镜,病理类型以上皮型多见,且常易被误诊为结核性胸膜炎。早期患者以手术治疗为主,而晚期患者以化疗为主,病理类型为上皮型的疾病控制率高于肉瘤型。结论恶性胸膜间皮瘤误诊率较高,其临床症状无特异性,胸部CT可提供诊断依据,组织病理学检查结合免疫组化才能确诊,治疗方式包括化疗、手术、放疗和支持治疗,普遍疗效欠佳。     

The therapeutic efficacy of anti vascular endothelial growth factor antibody, bevacizumab, and pemetrexed against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice.

PURPOSE: Malignant pleural mesothelioma (MPM) is an aggressive malignancy, which has a poor prognosis with a median survival of less than 1 year. The vascular endothelial growth factor (VEGF) has been reported to be an ideal therapeutic target, and a multitargeted antifolate, pemetrexed, has been clinically used for the treatment of MPM. EXPERIMENTAL DESIGN: We examined the therapeutic efficacy of the antihuman VEGF neutralizing antibody, bevacizumab, in combination with pemetrexed against two different human MPM cells, EHMES-10 and MSTO-211H, orthotopically inoculated into severe combined immunodeficient mice. RESULTS: Bevacizumab inhibited a VEGF-induced proliferation of the human endothelial cells in a dose-dependent manner, but it had no effect on the proliferation of the two MPM cell lines in vitro. The orthotopically inoculated EHMES-10 cells (VEGF high expressing) produced thoracic tumors and a large volume of bloody pleural effusion, whereas the MSTO-211H cells (VEGF low expressing) produced thoracic tumors and a small volume of bloody effusions. Treatment with bevacizumab effectively inhibited the production of thoracic tumors and dramatically prevented the production of pleural effusion by the EHMES-10 cells but not the MSTO-211H cells. Treatment with bevacizumab reduced the number of enlarged tumor-associated vessels and proliferating tumor cells. Moreover, treatment with bevacizumab in combination with pemetrexed more effectively suppressed the formation of the pleural effusion and prolonged the survival compared with the control and monotherapy in the EHMES-10 cell-bearing severe combined immunodeficient mice. CONCLUSIONS: These results suggest that the combined use of bevacizumab and pemetrexed may therefore be promising for controlling the progression of MPM highly expressing VEGF.