苦参黄酮抑制血管新生活性成分的虚拟筛选

血管新生是一个动态的、多步骤的过程,现在已知大约70种疾病与血管新生紊乱相关。作者前期研究及文献报道均表明苦参黄酮类成分有明显抑制血管新生的作用,但其药效物质基础和作用机制尚未明确。该研究应用分子对接技术虚拟筛选苦参黄酮抑制血管新生的药效物质,搜集现已分离鉴定的126个苦参黄酮类化合物组成配体数据库,选择VEGF-a,TEK,KDR等6个与血管新生密切相关的靶点组成受体数据库,以DrugBank中对各靶点有抑制作用并已上市的小分子药物为参照,设定各靶点对应的已上市小分子药物最低打分为阈值,应用Discovery Studio 2.5(DS2.5)软件的LibDock模块进行分子对接,虚拟筛选出打分高于阈值且排名前10%的化合物共37个。对比分析了原配体、已上市药物和苦参黄酮作用于各靶点的主要活性位点,初步揭示了苦参黄酮抑制血管新生的作用机制,为研发血管新生抑制剂类药物提供了一定的参考。     

基于斑马鱼模型探讨马钱子的抗血管生成活性

目的：以斑马鱼为模型,探讨马钱子的抗血管生成活性。方法：以Tg（kdrl:mCherry）斑马鱼和野生斑马鱼为模型,在安全浓度范围内,分别采用荧光显像和体内碱性磷酸酶定量检测的方法,以PTK787为阳性对照,考察马钱子水提取物对斑马鱼血管生成的抑制作用。结果：与空白对照组比较,在一定的浓度范围内,低浓度的马钱子水提取物能抑制Tg（kdrl:mCherry）斑马鱼的节间血管生成,随着提取物浓度的增加抑制作用更加明显,抑制作用呈剂量依赖性。在碱性磷酸酶定量检测实验中,马钱子水提取物浓度为25μg·mL^-1时,血管生成抑制率为8.61%;浓度为100μg·mL^-1时,血管生成抑制率为26.16%;在一定的浓度范围内,马钱子处理组均表现出显著的抗血管生成活性（P<0.05）,血管生成抑制率与马钱子水提取物浓度成线性关系。结论：马钱子水提取物可以有效的抑制斑马鱼血管生成,有明显的抗血管生成活性。     

影响安罗替尼临床疗效和预后的多因素分析

目的:观察经过安罗替尼治疗的不同瘤种恶性肿瘤患者的相关指标,探索影响安罗替尼临床疗效和预后的因素。方法:2018年7月至2019年12月使用安罗替尼治疗的晚期恶性肿瘤患者101例,取患者治疗过程中的血液,用ELISA法和实时荧光定量PCR法检测血清中VEGF、FGF、c-Kit、Bcl-2、PARP蛋白含量和mRNA相对表达量。另一方面,评价安罗替尼的疗效和随访观察PFS。结果:全部病例的总的中位PFS为4.8月（95%CI:3.8~5.8）,PR 18例（17.82%）,SD 61例（60.40%）,PD 22例(21.78%),ORR 17.82%,DCR 78.22%。TSH升高患者的DCR较未发生者高（P=0.039 0）。既往曾使用铂类化疗者较未使用者具有更长的中位PFS（5.3月 vs 3.6月,Log-rank P=0.038 0）,TSH升高患者较未升高患者的中位PFS显著延长（6.4月 vs 4.0月,Log-rank P=0.046 0）,发生手足综合征者中位PFS较未发生者显著延长（11.4月 vs 4.2月,Log-rank P=0.021 0）。血清bFGF的蛋白含量（P=0.009 0）及Bcl-2 mRNA相对表达量（P=0.012 0）是安罗替尼治疗晚期恶性肿瘤预后的独立影响因子。结论:血清bFGF含量及Bcl-2 mRNA表达量是安罗替尼疗效的独立影响因素;既往曾使用铂类、发生手足综合征和促甲状腺素升高者具有更长的PFS。     

Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer.

BACKGROUND: PKC412 (N-benzoyl-staurosporine), an oral inhibitor of protein kinase C, is capable of cell cycle inhibition and is endowed with anti-angiogenic properties. This dose-finding phase I study was designed to establish the maximum tolerated dose (MTD) of PKC412 when combined with cisplatin-gemcitabine. PATIENTS AND METHODS: Escalating doses of PKC412 were given every day of a 4 week cycle with cisplatin 100 mg/m2 on day 2 and gemcitabine 1000 mg/m2 on days 1, 8 and 15 in patients with non-small-cell lung cancer. Dose escalation was based on a modified continuous reassessment method. RESULTS: Twenty-three patients, assigned to four cohorts receiving PKC412 at a dose ranging from 25 to 150 mg/day were evaluable. Grade 3 diarrhea occurring in 3/4 patients at cycle 1 led us to define 150 mg/day as the MTD. The MTD based on multiple cycles was redefined as 100 mg/day, since prolonged grade 2-3 nausea/vomiting leading to treatment discontinuation occurred in 3/7 patients after repeated cycles. The next lower dose tested of 50 mg/day was therefore considered as the recommended dose for phase II trials. Among 33 cycles in eight patients, toxicity consisted of grade 1-2 diarrhea (12.5%) and asthenia (50%) with only one patient experiencing grade 3 headache at this dose level. A partial response was observed in three patients. CONCLUSIONS: The results of the present study indicate that PKC412 at a dose of 50 mg/day can be safely added to cisplatin and gemcitabine in patients with advanced non-small-cell lung cancer.     

抗血管生成酪氨酸激酶抑制剂治疗骨与软组织肉瘤的药物安全管理共识

抗血管生成靶向药物,特别是抗血管生成酪氨酸激酶抑制剂已在进展期骨肿瘤及软组织肉瘤中有广泛的应用,其中国产的阿帕替尼、安罗替尼等也通过全国单中心或多中心的临床研究证实有较好的疗效。但是,这类抗血管生成的靶向药物使用过程中所出现的不良反应,是限制这类药物发挥作用的关键。2019年8月中国骨肿瘤研究协作组成员进行充分的讨论,达成本共识,主要针对抗血管生成靶向药物在使用过程中常见的不良反应进行分类及处理,以期指导相关临床医生的用药管理,给更多使用抗血管生成靶向药物的患者带来生存受益。     

Our Experience After 1765 Intravitreal Injections of Bevacizumab: The Importance of Being Part of a Developing Story

This retrospective report describes our 20 months'experience using intravitreal injections of bevacizumab for the treatment of several retinal diseases. We describe our experience after 1765 intravitreal injections of bevacizumab in the treatment of different proliferative retinopathies – retinopathy of prematurity, choroidal neovascularization, diabetic retinopathy, among others. We believe that the findings reported in this study move us closer to a better treatment for different pathologies. However, further studies need to be performed in order to determine the safety and long-term efficacy of intravitreal bevacizumab either as first line therapy, after failure of conventional therapy, or in combination with conventional therapy.     

Nintedanib for the treatment of patients with advanced non-small-cell lung cancer

An unmet need remains for effective, well-tolerated treatment options in advanced non-small-cell lung cancer that can alleviate the disease burden for a broad selection of patients. Nintedanib (Vargatef) is a potent, oral, triple angiokinase inhibitor of three distinct pro-angiogenic pathways. A recent Phase III trial of second-line nintedanib plus docetaxel met the primary end point of progression-free survival and demonstrated significant benefit in the key secondary end point of overall survival, with median overall survival greater than 1 year for patients with adenocarcinoma histology. This article summarizes preclinical and clinical experience with nintedanib in non-small-cell lung cancer to date and discusses how it may be used in the future, including prospects for individualizing treatment by tumor proliferation dynamics and molecular biomarkers of response.     

三氧化二砷对鸡胚尿囊膜血管形成的抑制作用

背景与目的:三氧化二砷(As2O3)注射液,临床对肝癌等实体瘤的治疗具有一定的疗效,其作用机制有待阐明。本研究探讨三氧化二砷注射液对鸡胚尿囊膜(ch ick embryo chorioallantoic m embrane,CAM)血管生成的影响。方法:应用CAM模型和计算机图像分析技术,观察三氧化二砷注射液对血管形成的影响。结果:三氧化二砷注射液10、20和40μg/m l作用3 d后,CAM上的血管面积分别为(25.7±4.2)%、(24.7±2.5)%和(21.5±6.7)%,与生理盐水对照组[血管面积为(30.7±4.6]%]相比,差异有显著性(P<0.05,P<0.01,P<0.01);不同剂量组间比较,差异无显著性(P>0.05)。结论:三氧化二砷注射液对于CAM血管形成具有较强的抑制作用,可以研究试用于抗肿瘤血管形成治疗。     

Effect of antiangiogenic targeted chemotherapy on the osseointegration of titanium implants in rabbits

Patients with cancer have recently been treated with more advanced targeted chemotherapies that have greater specificity towards the cancer cells and fewer side effects. However, the periods of treatment take longer than those of traditional cytotoxic treatments. The aim of this study was to examine the effect of antiangiogenic targeted chemotherapy on the osseointegration of titanium implants. Fourteen white New Zealand rabbits were allocated randomly into two groups of seven: the placebo control group and the Avastin^® group. Animals in the Avastin^® group had five doses of bevacizumab intraperitoneally (3 mg/kg/week). The first was given two days before the implant was inserted and the remaining four were given weekly for four weeks. One titanium implant was inserted in the right distal femoral condyle of each rabbit. Osseointegration of the implants was measured using microcomputed tomography (CT) and histomorphometric evaluation. Both of these showed less osseointegration in the Avastin^® group than in the controls. The pharmacological inhibition of angiogenesis by bevacizumab may negatively affect the osseointegration of titanium implants in rabbits.