肿瘤抗血管生成疗法及相关药物的研究进展

目的 介绍肿瘤抗血管生成疗法的作用机制及近年抗血管生成药物研究进展。方法根据国内外的文献资料,进行整理归纳。结果 肿瘤血管生成主要与生长因子、溶解酶及炎症细胞特异性分子表达增加有关。研究证明许多天然或人工合成化学分子通过作用于上述血管增生反应中的特异性分子发挥抗肿瘤效应。结论 抗血管生成药物有望成为新一代抗肿瘤药。     

宫颈癌不同临床分期放疗抗拒与缺氧诱导血管新生的关系

目的探讨不同临床分期的宫颈癌放疗抗拒与肿瘤缺氧诱导血管新生的关系及意义。方法选取91例不同临床分期的宫颈鳞癌放疗患者,采用免疫组织化学SP法检测乏氧细胞诱导因子（HIF-1α）、血管内皮生长因子（VEGF）,并用CD105标记新生微血管密度（MVD）。结果随着临床分期的加重,肿瘤的放疗抗拒增大。VEGF、HIF—1α在宫颈鳞癌Ⅱb～Ⅳ期放疗后抗拒的阳性表达率升高,差异有统计学意义（P〈0．05）。HIF-1α、VEGF与MVD在不同临床分期之间存在正相关,且随临床分期的加重,MVD的计数逐渐增加,差异有统计学意义（P〈0．05）。结论随着宫颈鳞癌的临床分期加重,肿瘤的放疗抗拒加重,HIF-1α、VEGF、MVD的表达与之相关,可作为宫颈鳞癌放疗后判断预后的可靠依据。     

青蒿琥酯的抗血管生成作用

目的研究青蒿琥酯对血管生成的抑制作用。方法用人脐静脉内皮细胞(HUVEC)的生长、迁移及小管形成实验研究药物的体外抗血管生成作用;用人卵巢癌裸鼠移植瘤模型和免疫组化法研究药物的体内抗血管生成作用。结果青蒿琥酯浓度2.5 μmol·L^-1时,对HUVEC的增殖、迁移和小管形成均有显著的抑制作用;HUVEC 48 h的IC₅₀值为(21±3) μmol·L^-1。在整体实验中,青蒿琥酯50 mg·kg^-1·d^-1即可明显减少肿瘤的血管生成,抑制肿瘤生长;免疫组化结果表明,青蒿琥酯可以抑制VEGF和KDR/flk-1在肿瘤组织中的表达。结论青蒿琥酯有抗血管生成作用,提示该类药物在抗血管生成中有潜在的应用价值。     

血管内皮生长因子受体及其小分子抑制剂的研究进展

目前抗血管生成治疗是抗肿瘤研究的热点.血管内皮生长因子(VEGF)是刺激血管生成的重要因子之一,血管内皮生长因子受体(VEGFR)在肿瘤新生血管中高表达,因此成为肿瘤靶向治疗的理想靶点.以VEGF、VEGFR为靶点的抗肿瘤药物除了常见的单克隆抗体药物阿伐斯汀外,小分子抑制剂舒尼替尼、索拉非尼等也已经广泛使用;另外,一些...     

Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions

Introduction: The survival of patients with glioblastoma (GBM), which is the most common primary brain malignancy, remains poor with current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes.

Areas covered: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) initiate key signaling pathways in GBM; however, trials with anti-EGFR agents have failed to show improved outcomes. Bevacizumab, a monoclonal antibody targeting VEGF, remains the only FDA-approved molecular drug in GBM; yet its use has only improved progression-free survival without any improvement in overall survival. We review the evidence supporting the continued evaluation of targeted molecular therapies in recurrent GBM. In addition, newer potential therapies targeting other signaling pathways, heat shock proteins and proteosomes, as well as the concept of targeting glioma stem cells are discussed.

Expert opinion: The complex genetic origin of GBM makes it challenging to identify molecular subsets that may benefit from specific targeted therapies. Pathway inhibition, via multisite kinase inhibitors or a carefully selected combination of molecular drugs with or without cytotoxic agents, is currently undergoing evaluation in clinical trials and may improve outcomes in these patients.     

桂枝茯苓丸联合米非司酮治疗子宫肌瘤的疗效及对患者血清孕激素受体、雌激素受体和血管内皮生长因子的影响

目的 研究桂枝茯苓胶囊联合米非司酮治疗子宫肌瘤的疗效及对患者血清孕激素受体（PR）、雌激素受体（ER）、血管内皮生长因子（VEGF）的影响。方法 选取2014年1月-2017年6月西安市北方医院妇产科收治的子宫肌瘤患者75例,随机分为对照组、观察组,各38、37例。对照组于月经的第3天口服米非司酮片12.5 mg,每天1次,于每晚睡前口服;观察组在对照组基础上于月经的第1天口服桂枝茯苓胶囊3粒,每天3次,疗程3个月。比较两组的临床治疗效果,比较两组治疗前后的子宫肌瘤体积、月经量以及子宫体积,以及血清ER、PR、VEGF水平变化。结果 观察组的有效率为94.59%（35/37）,明显高于对照组的71.05%（27/38）,差异有统计学意义（P<0.05）。两组治疗3个月后的子宫肌瘤体积、月经量以及子宫体积均明显降低,同组治疗前后比较差异有统计学意义（P<0.05）,且观察组以上指标明显低于对照组,差异有统计学意义（P<0.05）。两组治疗3个月后的血清ER、PR、VEGF水平均明显降低,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组以上指标明显低于对照组,差异有统计学意义（P<0.05）。所有患者均未出现低血压、体质量显著增加以及色素沉着等不良反应。结论 桂枝茯苓胶囊联合米非司酮对子宫肌瘤患者具有较为确切的治疗效果,不仅可以有效缩小子宫肌瘤体积以及子宫体积,还可以降低血清ER、PR、VEGF水平。     

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。     

子宫肌瘤患者手术并发症临床分析

目的:探讨预防和减少子宫肌瘤患者手术治疗并发症的方法.方法:回顾性分析624例子宫肌瘤患者术后发生并发症18例的临床资料.结果:18例患者主要有切口愈合不良、下肢深静脉血栓形成、呼吸道感染、泌尿系感染、尿潴留等并发症,发生率分别为1.60%、0.16%、0.64%、0.32%、0.16%.结论:严格掌握手术指征,采取必要措施,才能避免或减少手术并发症,提高患者术后生活质量.     

Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales

Angiogenesis, a process of new blood vessel formation, is a prerequisite for tumour growth to supply the proliferating tumour with oxygen and nutrients. The angiogenic process may contribute to tumour progression, invasion and metastasis, and is generally accepted as an indicator of tumour prognosis. Therefore, targeting tumour angiogenesis has become of high clinical relevance. The current review aimed to highlight mechanistic details of anti-angiogenic therapies and how they relate to classification and treatment rationales. Angiogenesis inhibitors are classified into either direct inhibitors that target endothelial cells in the growing vasculature or indirect inhibitors that prevent the expression or block the activity of angiogenesis inducers. The latter class extends to include targeted therapy against oncogenes, conventional chemotherapeutic agents and drugs targeting other cells of the tumour micro-environment. Angiogenesis inhibitors may be used as either monotherapy or in combination with other anticancer drugs. In this context, many preclinical and clinical studies revealed higher therapeutic effectiveness of the combined treatments compared with individual treatments. The proper understanding of synergistic treatment modalities of angiogenesis inhibitors as well as their wide range of cellular targets could provide effective tools for future therapies of many types of cancer.     

128层螺旋CT血管重建在子宫肌瘤和卵巢肿瘤鉴别诊断中的应用价值

目的探讨128层螺旋CT血管重建在子宫肌瘤和卵巢肿瘤鉴别诊断中的临床价值。方法2013年1月至2013年10月期间，巴中市中心医院手术病理证实的30例卵巢肿瘤患者和30例子宫肌瘤患者作为研究对象，通过128层螺旋CT扫描检查仪，进行CT平扫、CT增强扫描，对两组卵巢静脉显示率、卵巢动脉显示率、子宫动脉显示率，进行观察和比较。结果与子宫肌瘤组相比，卵巢肿瘤组卵巢静脉显示率、卵巢动脉显示率均明显提高，P〈0．05，差异有统计学意义；而子宫动脉显示率，两组差异没有统计学意义，P〉0．05。结论128层螺旋CT扫描检查能够清晰显示肿瘤供血情况，有助于子宫肌瘤和卵巢肿瘤的鉴别诊断。     

丙泊酚复合芬太尼在射频治疗子宫肌瘤和子宫功能性出血的疗效观察

目的：观察丙泊酚复合芬太尼在射频治疗子宫肌瘤和子宫功能性出血中的疗效。方法：对120例子宫肌瘤和子宫功能性出血患者在常规消毒后，先静脉滴注芬太尼0．1mg、地塞水松5mg和阿托品0．5mg。3分钟后在牵拉子宫颈前静脉推注丙泊酚50-60mg，术中根据患者反应持续推注丙泊酚.术中用多功能生理监测仪分别记录推药前、入睡后、手术时、NNNBP、P、RR、SpO2参数。观察麻醉效果。结果：丙泊酚复合芬太尼应用于射频治疗子宫肌瘤术，起效快，镇痛效果显著，有效率达100％。苏醒早。BP、P、RR、SpO2参数无明显变化。结论：丙泊酚复合芬太尼静脉麻醉是射频治疗子宫肌瘤和子宫功能性出血的较好麻醉方法．可达到良好的镇静和镇痛效果。     

VEGF通路和Notch通路在肿瘤血管生成中的相互作用及靶向药物的研发

综述VEGF通路和Notch通路在肿瘤血管生成中的作用,重点阐述两者的相互作用在肿瘤血管形成中的意义,并概述以这两条信号通路为靶点的抗肿瘤药物研发现状。     

Prospective analysis of the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-based therapy in metastatic breast cancer patients

AIMS

To test prospectively the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-chemotherapy in breast cancer patients.

METHODS

As part of the single-arm MO19391 trial, 137 women with locally recurrent or metastatic breast cancer receiving first-line bevacizumab-containing therapy were analysed. Patients received bevacizumab associated (76%) or not (24%) with taxane-based chemotherapy. Clinical evaluation included clinical response, time to progression (TTP) and a toxicity score corresponding to the sum of each maximum observed toxicity grade (hypertension, haemorrhage, arterial and venous thrombo-embolism). Functional VEGF-A polymorphisms at position −2578 C > A, −1498 T > C, −1154 G > A, −634 G > C and 936 C > T were analysed by PCR-RFLP (blood DNA).

RESULTS

Overall response rate (complete response (CR) + partial response (PR)) was 61%. Median TTP was 11 months. None of the VEGF-A polymorphisms was significantly linked to clinical response. Analysis of the 936C > T polymorphism revealed that the 96 patients homozygous for the 936C allele exhibited a marked tendency for a shorter TTP (median 9.7 months) than the 32 patients bearing the 936T allele (median 11.5 months, P = 0.022) of which 30 were CT and two were homozygous TT. Other polymorphisms did not influence TTP. VEGF-A−634 G > C was significantly related to the toxicity score with 39%, 49% and 81% of patients with score >1 in GG, GC and CC patients, respectively (P = 0.01).

CONCLUSIONS

The role for VEGF-A 936C > T polymorphism as a potential marker of TTP in breast cancer patients receiving bevacizumab-containing therapy concords with the known impact of VEGF-A 936C > T polymorphism on VEGF-A expression.     

抗肿瘤血管新药的研究进展

目前肿瘤血管靶向治疗新药的研究主要集中在两个方向,即肿瘤血管生成抑制剂(tumor angiogenesis inhibitor,TAI)和肿瘤血管靶向制剂(vascular targeting agent,VTA).TAI类旨在抑制肿瘤血管生成的过程,近年来研究较多的为血管内皮生长因子(VEGF)类、基质金属蛋白酶(MMP)类、血管抑素类、内皮抑素类等;而VAT类则是通过破坏肿瘤组织中已存在的血管从而使肿瘤坏死,主要包括小分子类VTA和生物类VTA.对近年来各类抗肿瘤血管治疗新药的种类、作用机制及各自的临床研究进展进行综述.     

基于结构设计的新型mTOR抑制剂的抗宫颈癌活性研究（英文）

激酶mTOR是PI3K-AKT信号通路的关键组成部分,该激酶在宫颈癌细胞中被高度激活。本文运用基于结构的药物发现等手段发现了一系列mTOR激酶抑制剂并对其进行生物学评价,发现其可发挥有效的抗宫颈癌作用。酶活性测定结果显示化合物C3具有潜在的mTOR抑制作用(IC₅₀=1.57μM)。随后利用分子对接和动力学模拟探究并预测m TOR激酶和C3的结合模式,初步探讨了化合物的构效关系。在多种肿瘤细胞系上进行细胞增殖活性实验时发现,C3对宫颈癌细胞He La表现出较好的增殖抑制活性(IC₅₀=0.38μM)。此外, C3还能浓度依赖性地降低磷酸化核糖体S6 (p-S6)蛋白在HeLa细胞内的表达水平。值得注意的是,C3发挥显著的抗宫颈癌活性很有可能是mTOR通路和其他细胞内通路的共同作用。本研究表明C3可进一步开发为宫颈癌的治疗药物。     

肿瘤血管生成抑制剂筛选模型的研究进展

目的:介绍肿瘤血管生成抑制剂(tumor angiogenesis inhibitor,TAI)筛选模型的研究进展。方法:查阅国内外相关文献进行分析和归纳。结果:TAI的筛选主要依赖于采用形态学检测法测定血管的生成活性。TAI筛选的程序为:体外筛选→体内筛选→应用肿瘤模型进行全面最终的评价。结论:TAI对于肿瘤治疗有重要作用,其筛选模型的研究取得突破性进展。     

Effects of cyclooxygenase 2 inhibitors on biological traits of nasopharyngeal carcinoma cells

AIM: To investigate effects of cyclooxygenase 2 (COX-2) inhibitors on nasopharyngeal carcinoma (NPC) cells and on angiogenesis in vitro. METHODS: Human NPC cell lines (CNE1, CNE2 and SUNE) were treated with nimesulide or celecoxib. MTT assay and colony formation assay were performed to observe antiproliferation activity of COX-2 inhibitors to NPC cell lines. Cell cycle arrest and apoptosis of NPC cell strains were tested by flow cytometry assay, microscopic morphology observation, and DNA fragmentation assay. The effect of COX-2 inhibitor on angiogenesis was tested by chick chorioallantoic membrane (CAM) model. RESULTS: Nimesulide (Nim) and celecoxib (Cel) could antiproliferate NPC cell lines with IC50 182 μmo1/LNim-SUNE, 78 vmol/LNim-CNE1, 175μmoI/LNim-CNE2, 7.2 μmol/LCet-SUNE, 8.1 μmoI/LCet-CNE1, and 7.6 μmol/LCet-CNE2. The antiproliferation presented dose-dependent (Nim 5-400 μmol/L, Cel 0.5-80 μmol/L) and time-dependent manner (Nim IC50 562 μmol/L24 h, 316 μmol/L 48 h,50.1 μmol/L240h). Nim and Cel arrested SUNE and CNE1 cell cycle at phase G2/M (cell aggregation rate 28.9 %-45.1%y.Nim25-200μmol-12h-SUNM,18.9 %-26.2 %Nim25-200μmol-24h-SUNM, 28.8%-35.6 %Nim25-200μmol-48h-SUNM,30.4 %-16.4 %Nim25-200μmol-12h-SUNM,21.2 %-19.7 %Nim25-200μmol-24h-SUNM, 31.1%- 19.9%Nim25-200μmol-12h-SUNM, 20.5 %-34.1%Nim25-200μmol-12h-SUNM,25.2 %-26.9 %Nim25-200μmol-12h-SUNM, 11.5 %-7.1% Nim25-200μmol-12h-SUNM,Apoptosis shape and apoptosis strap displayed in NPC cells after treatment with Nim and Cel. Nim had a feature of anti-angiogenesis on CAM model. CONCLUSION:Nim and Cel could suppress proliferation of squamous epithelium NPC cell (SUNE, CNE1 and CNE2) through blocking cell cycle and inducing cell apoptosis. Nim could apparently suppress CAM angiogenesis induced bySUNE cell.     

Recent advances in,and challenges of,anti-angiogenesis agents for tumor chemotherapy based on vascular normalization

A major problem associated with cancer treatment is resistance-prone chemotherapeutic drugs. An increasing number of studies have documented that the occurrence of resistance tends to be associated with abnormal blood vessels. In 2001, Jain proposed the vascular normalization theory, which was recently applied to the drug-resistant treatment of tumors in the clinic. Through the intervention of angiogenesis inhibitors, remodeling the structure and function of abnormal vessels can maximize the efficacy of chemotherapeutic drugs. In this review, we systematically describe the occurrence and progress of tumor angiogenesis, as well as the pathological characteristics of tumor blood vessels. Moreover, druggable targets for vascular normalization and the development of related inhibitors are also outlined.     

贝伐珠单抗应用分析与合理性评价

目的：了解贝伐珠单抗在肿瘤治疗中的临床应用现状。方法：对其院2015年1月-2016年1月期间使用过贝伐珠单抗的209例患者,897次用药情况进行回顾性分析,按原发疾病分类,参考说明书及药品信息对患者治疗情况进行统计、评价及安全性评估。结果：209例患者数据分析中显示,适应证应用基本符合中国CFDA、美国FDA审批批准的范围,说明书内适应证治疗用药比例为53.73%,超说明书用药比例为46.27%,其中包含FDA批准适应证、NCCN指南推荐及其他超说明书用药。贝伐珠单抗应用期间所出现的不良反应（ADR）基本与说明书相符。结论：贝伐珠单抗超说明书应用普遍存在,部分超说明书应用有一定的循证学依据。应加强对超说明书用药的监管规范,确保药物安全合理使用。