肿瘤血管生成机制及抗肿瘤血管新生的靶向药物研究进展

抗肿瘤血管新生治疗是以血管内皮细胞为靶点,通过降低血管活性因子的活性、抑制内皮细胞增殖和迁移、改变肿瘤生长微环境,从而抑制肿瘤生长过程中的血管新生,切断肿瘤的供养,最终达到遏制肿瘤生长和转移的目的,是一种全新的靶向肿瘤治疗方法.该方法具有高效特异性、不易产生耐药性、药物易于到达靶部位和毒副作用小等优点,可以有效地抑制肿瘤的转移和复发,现在已成为抗肿瘤血管生成药物研究的热点之一,该文综述了肿瘤血管生成的机制及抗血管新生治疗药物的最新研究进展.     

Anti-angiogenic efficacy of 5′-triphosphate siRNA combining VEGF silencing and RIG-I activation in NSCLCs

Short interfering RNA (siRNA) targeting angiogenic factors and further inhibiting tumor angiogenesis, is one of the potent antitumor candidates for lung cancer treatment. However, this strategy must be combined with other therapeutics like chemotherapy. In this study, we designed a 5′-triphosphate siRNA targeting VEGF (ppp-VEGF), and showed that ppp-VEGF exerted three distinct antitumor effects: i) inhibition of tumor angiogenesis by silencing VEGF, ii) induction of innate immune responses by activating RIG-I signaling pathway, and thus activate antitumor immunity, iii) induction of apoptosis. In a subcutaneous model of murine lung cancer, ppp-VEGF displayed a potent antitumor effect. Our results provide a multifunctional antitumor molecule that may overcome the shortages of traditional antiangiogenic agents.     

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.     

Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen

Angiostatin, a potent inhibitor of angiogenesis, tumour growth and metastasis, is a biologically active fragment of plasminogen, containing the kringle domains 1-4. It is generated from plasminogen by limited proteolysis. We show that prostate-specific antigen (PSA), a serine proteinase secreted by human prostate and human prostate cancer cells, is able to convert Lys-plasminogen to biologically active angiostatin-like fragments, containing kringles 1-4, by limited proteolysis of peptide bond Glu439-Ala440 in vitro. In an in vitro morphogenesis assay, the purified angiostatin-like fragments inhibited proliferation and tubular formation of human umbilical vein endothelial cells with the same efficacy as angiostatin. This finding might help to understand growth characteristics of prostate cancer, which usually has low microvessel density and slow proliferation.     

Pleiotropic Effects of Herbs Characterized with Blood-Activating and Stasis-Resolving Functions on Angiogenesis

Accumulative evidences have underpinned the nature candidates from Chinese medicine (CM), particularly CM served as blood activating and stasis resolving (BASR, Huoxue Huayu in Chinese) by targeting tumor-associated angiogenesis. However, recent experiment research on the therapeutic angiogenesis by BASR-CM attracts wide attention and discussion. This opinion review focused on the underlying link between two indications and anticipated that (1) BASR-CM might emphasize on a balanced multi-cytokines network interaction; (2) BASR-CM might address on the nature of diseases prior to differently affecting physiological and pathological angiogenesis; (3) BASR-CM might mainly act on perivascular cells, either promotes arteriogenesis by increasing arteriogenic factors in ischemic diseases, or simultaneously keep a quiescent vasculature to impede angiogenesis in tumor context.     

阿帕替尼治疗晚期胰腺癌的疗效和安全性及疗效预测指标的探索北大核心

目的:观察甲磺酸阿帕替尼治疗晚期胰腺癌的疗效与安全性,探索血清血管内皮生长因子(vascular endothelial growth factor,VEGF)和血管内皮生长因子受体-2(vascular endothelial growth factor receptor-2,VEGFR-2)水平与阿帕替尼疗效的关系。方法:本课题选择经病理确诊一线治疗进展后无法耐受或不愿接受二线化疗的晚期胰腺癌患者,经知情同意后给予阿帕替尼500 mg po qd治疗,2周期评估一次,主要观察指标为疾病控制率(disease control rate,DCR),次要观察指标为无进展生存期(progression-free survival,PFS)和不良反应;应用ELISA法检测治疗前患者血清VEGF和VEGFR-2水平;卡方检验分析血清VEGF和VEGFR-2水平与阿帕替尼疗效的关系。结果:本课题共入组24例一线治疗进展的晚期胰腺癌患者,可评估患者共23例。其中完全缓解(complete response,CR)0例、部分缓解(partial response,PR)1例(4.35%)、疾病稳定(stable disease,SD)8例(34.78%)、疾病进展(progressive disease,PD)14例(60.87%)。DCR为39.13%,中位PFS为2个月。阿帕替尼在治疗过程中出现的不良反应按照发生频率依次为乏力(91.30%)、高血压(52.17%)、口腔黏膜炎(52.17%)、蛋白尿(47.83%)、贫血(43.48%)、腹泻(21.74%)、呕吐(17.39%)、消化道出血(4.35%)、陈旧伤口裂开(4.35%)。在SD组和PD组中血清VEGF和VEGFR-2水平并没有明显差异。结论:对于一线治疗进展并且体力状况良好的晚期胰腺癌患者,阿帕替尼可以作为一个可选的治疗策略,血清VEGF和VEGFR-2水平不能预测阿帕替尼疗效。     

软骨细胞培养液对鸡胚绒毛尿囊膜血管抑制效应的研究

目的检测软骨细胞培养液中是否存在抑制血管生长的因子。方法用酶消化、分离鸡胚关节软骨细胞,体外单层培养,收集细胞培养液。采用鸡胚绒毛尿囊膜实验检测该培养液对血管的抑制效应。结果加软骨细胞培养液的实验组血管数为2.75±0.99且血管较细、分支少;不加样的对照组血管数为4.5±1.08且血管较粗、分支多。两组有显著差异(P＜0.05)结论软骨细胞培养液具有抑制血管生长的作用。     

Transpupillary thermotherapy (TTT) for age-related macular degeneration

Purpose. To review the results of transpupillary thermotherapy (TTT) on choroidal neovascular membranes associated with age-related macular degeneration (AMD). Materials and Methods. 35 eyes of 35 patients with AMD and choroidal neovascularization and exudation were treated with TTT and had fundus photographs and fluorescein angiography (FA) before and at least six months after TTT. 28 eyes had predominantly occult lesions as seen on FA, while 7 demonstrated primarily classic lesions. All were treated with 650 mw power or less using the 810 nm diode laser (3000 micron spot, duration of 60 seconds). Visual acuity, lesion size, and amount of subretinal fluid were determined by results of examination and review of photographs and fluorescein angiograms. Results. A 50% reduction in subretinal fluid was achieved in 67% of treated eyes overall, with stabilization of vision (less than three lines of visual acuity lost) in 86%. Complications from treatment were infrequent (9%) and involved hemorrhage noted in the region of treatment upon follow-up. Conclusion. TTT promotes resolution of subretinal fluid and appears to stabilize visual acuity in patients with exudative AMD.     

DCLAK11, a multi-tyrosine kinase inhibitor,exhibits potent antitumor and antiangiogenic activity in vitro

Aim:

To investigate the molecular targets of DCLAK11, a novel compound discovered from a series of substituted pyridin-3-amine derivatives, and to characterize its anti-tumor properties in vitro.

Methods:

Kinase inhibition was measured by an ELISA assay. Cell viability was assessed with an SRB or a CCK8 assay. The alterations induced by kinase signaling proteins in cancer cells were detected by Western blot. Apoptosis was determined by an Annexin V-PI assay. The following assays were used to evaluate the impact on angiogenesis: wound-healing, Transwell, tube formation and microvessel outgrowth from rat aortic rings.

Results:

DCLAK11 was a multi-targeted kinase inhibitor that primarily inhibited the EGFR, HER2, and VEGFR2 tyrosine kinases with IC₅₀ value of 6.5, 18, and 31 nmol/L, respectively. DCLAK11 potently inhibited the proliferation of EGFR- and HER2-driven cancer cells: its IC₅₀ value was 12 and 22 nmol/L, respectively, in HCC827 and HCC4006 cells with EGFR exon deletions, and 19 and 81 nmol/L, respectively, in NCI-N87 and BT474 cells with HER2 amplification. Consistently, DCLAK11 blocked the EGFR and HER2 signaling in cancer cells with either an EGFR or a HER2 aberration. Furthermore, DCLAK11 effectively induced EGFR/HER2–driven cell apoptosis. Moreover, DCLAK11 exhibited anti-angiogenic activity, as shown by its inhibitory effect on the proliferation, migration and tube formation of human umbilical vascular endothelial cells and the microvessel outgrowth of rat aortic rings.

Conclusions:

DCLAK11 is a multi-targeted kinase inhibitor with remarkable potency against tyrosine kinases EGFR, HER2 and VEGFR2, which confirms its potent anti-cancer activity in EGFR- and HER2-addicted cancers and its anti-angiogenic activity.