人内皮抑素基因导入对裸鼠舌鳞癌移植瘤的抑制影响

目的:探讨经体内注入人内皮抑素(humanendostatin,hES)基因治疗口腔鳞癌的可行性。方法:荷瘤人舌鳞癌Tca8113细胞裸鼠瘤体内和肌内分别注射含hES的基因质粒,观察转入hES基因对舌鳞癌移植瘤生长的影响,免疫组织化学检测肿瘤组织中hES及血管内皮细胞生长因子(vascularvesselendotheliacellgrowthfactor,VEGF)的表达,Weidern法行肿瘤微血管密度(microvesseldensity,MVD)计数,流式细胞仪检测肿瘤细胞凋亡率,采用精确概率法和单因素方差分析进行统计学处理。结果:荷瘤注射hES后第16天,瘤体注射组抑瘤率为75.0%,肌内注射组抑瘤率为66.1%(P<0.01)。免疫组织化学检测结果显示,hES在瘤体注射组和肌内注射组肿瘤中的表达率分别为90.0%和85.0%,均高于对照组的20.0%(P<0.01)。2实验组肿瘤MVD值分别为18.60±3.44和16.70±2.63,均低于对照组的22.40±3.41(P<0.01)。流式细胞仪检测发现,瘤体注射和肌内注射hES基因质粒后,肿瘤细胞凋亡率分别为11.36%±3.20%和8.08%±2.00%,均高于对照组的1.80%±0.50%(P<0.01)。结论:注射hES基因具有抑制舌鳞癌Tca8113细胞移植瘤生长的效应。     

重组人血管内皮抑制素在晚期肺鳞癌治疗中的临床应用

背景与目的肺鳞癌是非小细胞肺癌常见的病理类型,晚期肺鳞癌是一种无法治愈的恶性肿瘤。抗血管生成药物与传统化疗联合能够为患者带来生存改善。本研究分析了重组人血管内皮抑制素（恩度）联合化疗治疗晚期肺鳞癌的疗效及安全性。方法回顾性分析中国医学科学院肿瘤医院内科2011年11月-2015年5月采用人血管内皮抑制素联合传统化疗方案治疗的15例晚期肺鳞癌患者的近期疗效、毒副反应及无进展生存时间。结果14例可评估患者中疗效评价最佳即为部分缓解5例（35.7%）、疾病稳定7例（50.0%）、疾病进展2例（14.3%）,客观缓解率为35.7%,疾病控制率为85.7%,中位无进展生存为9.3个月。全组患者治疗耐受良好,3度不良反应表现为中性粒细胞减少（2/15,13.3%）和呕吐（1/15,6.7%）,其余不良事件均为1度/2度。结论重组人血管内皮抑制素联合化疗治疗晚期肺鳞癌可取得较好的客观疗效并且安全性良好。     

合欢皮皂苷物质的分离、纯化及其抗血管活性的研究

目的 分离合欢皮中的皂苷物质,并评价其对人脐静脉内皮细胞(EA.hy926)增殖的影响.方法 以细胞活性为指标,依次采用D101大孔树脂、硅胶柱、反相C18色谱柱从合欢皮正丁醇相中分离得到活性组分H5;采用UPLC-TOF-MS分析,确定此组分中所含的主要成分.结果 组分H5中主要皂苷类物质为julibroside J5、julibroside J8、isomer of J5和isomer of J8,总含量为79.15％,且对EA.hy926细胞的增殖具有抑制作用(IC50=7.82 ±1.59 μg·mL-1).结论 成功分离得到了具有抗血管新生作用的合欢皮皂苷物质.     

可溶性血管内皮生长因子受体1真核克隆表达及其对血管内皮细胞增殖的影响

本研究旨在构建可溶性血管内皮生长因子(vascular endothelial growth factor,VEGF)受体1(soluble fmslike tyosine kinase-1,sFlt-1)的真核表达质粒pcDNA3.1-sFlt-1,并观察sFlt-1对血管内皮细胞增殖的影响。提取人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVECs)总RNA,扩增Flt-1基因胞外1-3结构域,构建真核表达质粒pcDNA3.1-sFlt-1,测序鉴定基因序列。将重组质粒转染Lewis肺癌细胞,采用RT-PCR和SDS-PAGE检测sFlt-1在基因及蛋白水平的表达情况。MTT法检测sFlt-1对VEGF诱导的HUVECs生长的影响。结果显示:①插入片段序列正确;②sFlt-1在基因水平成功表达且转染后的Lewis肺癌细胞能分泌表达sFlt-1;③含sFlt-1的细胞上清液可明显抑制VEGF诱导的HUVECs增殖。本研究成功构建了真核表达质粒pcDNA3.1-sFlt-1,sFlt-1,在基因和蛋白水平均获得有效表达,且表达的蛋白可明显抑制由VEGF诱导...     

Tumor progression-dependent angiogenesis in gastric cancer and its potential application

Despite improvements in the early diagnosis, prognosis and therapeutic strategies for gastric cancer (GC), human GC remains one of the most frequently diagnosed malignant tumors in the world, and the survival rate of GC patients remains very poor. Thus, a suitable therapeutic strategy for GC is important for prolonging survival. Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis, including angiogenesis, inflammation, immunosuppression and metastasis. Importantly, these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch. The development, relapse and spreading of tumors depend on new vessels that provide the nutrition, growth factors and oxygen required for continuous tumor growth. Therefore, a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis. Recently, several antiangiogenic agents have been identified, and their potential for the clinical management of GC has been tested. Here, we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC. We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor (VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC. However, most antiangiogenic agents have reported no benefit to overall survival (OS) compared to chemotherapy alone in local or advanced GC. In phase III clinical trials, only ramucirumab (anti-VEGFR blocker) and apatinib (VEGFR-TKI blocker) have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2nd-line agent combined with chemotherapy treatment in advanced GC. By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC, this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.     

Novel treatment options in platinum-sensitive recurrent ovarian cancer: A review

Epithelial ovarian cancer (EOC) is the leading cause of death due to gynecologic malignancy. The majority of advanced stage EOC patients, even those who respond well to frontline therapy, will ultimately recur and succumb to their disease. In platinum-sensitive EOC patients, or those who recur ≥6?months from initial diagnosis, treatment of recurrent disease has traditionally consisted of repeat platinum-based chemotherapy. Secondary cytoreduction remains controversial. Due to recent advances in molecularly targeted treatment options, outcomes for advanced stage EOC patients are significantly improving and hold great promise. This review discusses pivotal trials establishing platinum-based combination chemotherapy as the standard of care and addresses the utility of increasing a patient's platinum-free interval. It then discusses the role of anti-angiogenesis therapeutics, specifically bevacizumab, cediranib, and trebananib and their side effects. Lastly, it reviews key trials for the three poly-adenosine diphosphate [ADP]-ribose polymerases (PARP) inhibitors that have been FDA-approved for maintenance therapy in platinum-sensitive recurrent EOC: olaparib, rucaparib, and niraparib. This review concludes with a discussion regarding ongoing and future clinical trials.     

抗肿瘤血管生成药物致高血压的临床观察

目的 探讨肿瘤患者在进行抗肿瘤血管生成治疗的过程中高血压发生率及处理方式,研究影响患者高血压发生的因素.方法 随机选取抗肿瘤血管生成治疗的患者180例,按性别分成2组.抗肿瘤血管生成常见治疗药物:和化疗联合的贝伐单抗,进行单药治疗的索拉非尼、依维莫司、阿昔替尼、舒尼替尼.观察治疗过程中患者高血压发生情况,使用NCI-CTC AE 3.0,把它作为评估患者高血压程度的依据,根据不同级别采取相应的降压治疗措施.最后采用Logistic多元回归分析和单因素分析的方法,分析影响高血压发生的因素.结果 180例恶性肿瘤患者在行抗肿瘤血管生成药物治疗的过程中,高血压的发生率为30%,Ⅲ级发生率为46%.经相应的降压治疗措施后血压均恢复稳定,避免了高压危象的出现.经记录发现患者发生高血压的首次中位时间最早为5.0天,发生重度高血压的中位时间最早为12.0天.既往有高血压史患者及肾癌患者发生高血压的风险要远远高于无既往高血压患者及其他类型的恶性肿瘤患者,其差异具有统计学意义(P<0.05).结论 抗肿瘤血管生成药物致恶性肿瘤患者高血压的出现率较高.对中度高血压,采用降压药物治疗效果较为显著.     

Anti-Angiogenic Activity of Gecko Aqueous Extracts and its Macromolecular Components in CAM and HUVE-12 Cells

Gecko is a kind of traditional Chinese medicine with remarkable antineoplastic activity. However, undefinedmechanisms and ambiguity regarding active ingredients limit new drug development from gecko. This study wasconducted to assess anti-angiogenic properties of the aqueous extracts of fresh gecko (AG) or macromolecularcomponents separated from AG (M-AG). An enzyme-linked immunosorbent assay (ELISA) approach wasapplied to detect the vascular endothelial growth factor (VEGF) secretion of the tumor cells treated with AG orM-AG. The effect of AG or M-AG on vascular endothelial cell proliferation and migratory ability was analyzedby tetrazolium dye colorimetric method, transwell and wound-healing assays. Chick embryo chorioallantoicmembrane (CAM) assays were used to ensure the anti-angiogenic activity of M-AG in vivo. The results showedthat AG or M-AG inhibited the VEGF secretion of tumor cells, the relative inhibition rates of AG and M-AGbeing 27.2% and 53.2% respectively at a concentration of 20 μL/mL. AG and M-AG inhibited the vascularendothelial (VE) cell proliferation with IC50 values of 11.5±0.5 μL/mL and 12.9±0.4 μL/mL respectively. TheVE cell migration potential was inhibited significantly (p<0.01) by the AG (≥24 μL/mL) or M-AG (≥12 μL/mL) treatment. In vivo, neovascularization of CAM treated with M-AG was inhibited significantly (p<0.05)at a concentration of 0.4 μL/mL. This study provided evidence that anti-angiogenesis is one of the anti-tumormechanisms of AG and M-AG, with the latter as a promising active component.     

Thyroid hormone as a regulator of tumor induced angiogenesis

Thyroid hormones (TH) – 3,5,3′-triiodo-l-thyronine (T₃) and l-thyroxine (T₄) – are important regulators of differentiation, growth, metabolism, and physiological function in most tissues. TH have been also implicated in cellular transformation, tumorigenesis and metastasis, assuming particular importance in tumor induced angiogenesis. TH-induced angiogenesis is thought to be initiated at integrin αvβ3 membrane receptor mainly through T₄ binding. The reduction of TH in circulation or the inhibition of TH actions at the integrin αvβ3 receptor would consequently produce a reduction on the proliferative and angiogenic TH effects. Therefore, targeting TH actions could be an alternative adjuvant therapy against cancer proliferation and angiogenesis.     

Enhancement of radiation response with bevacizumab

ABSTRACT: BACKGROUND: Vascular endothelial growth factor (VEGF) plays a critical role in tumor angiogenesis. Bevacizumab is a humanized monoclonal antibody that neutralizes VEGF. We examined the impact on radiation response by blocking VEGF signaling with bevacizumab. METHODS: Human umbilical vein endothelial cell (HUVEC) growth inhibition and apoptosis were examined by crystal violet assay and flow cytometry, respectively. In vitro HUVEC tube formation and in vivo Matrigel assays were performed to assess the anti-angiogenic effect. Finally, a series of experiments of growth inhibition on head and neck (H&N) SCC1 and lung H226 tumor xenograft models were conducted to evaluate the impact of bevacizumab on radiation response in concurrent as well as sequential therapy. RESULTS: The anti-angiogenic effect of bevacizumab appeared to derive not only from inhibition of endothelial cell growth (40%) but also by interfering with endothelial cell function including mobility, cell-to-cell interaction and the ability to form capillaries as reflected by tube formation. In cell culture, bevacizumab induced a 2 ~ 3 fold increase in endothelial cell apoptosis following radiation. In both SCC1 and H226 xenograft models, the concurrent administration of bevacizumab and radiation reduced tumor blood vessel formation and inhibited tumor growth compared to either modality alone. We observed a siginificant tumor reduction in mice receiving the combination of bevacizumab and radiation in comparison to mice treated with bevacizumab or radiation alone. We investigated the impact of bevacizumab and radiation treatment sequence on tumor response. In the SCC1 model, tumor response was strongest with radiation followed by bevacizumab with less sequence impact observed in the H226 model. CONCLUSIONS: Overall, these data demonstrate enhanced tumor response when bevacizumab is combined with radiation, supporting the emerging clinical investigations that are combining antiangiogenic therapies with radiation.