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121.
Yao Yu Jing Yu Chong Gang Pei Yun Yan Li Ping Tu Gui Ping Gao Yi Shao 《International journal of clinical and experimental pathology》2015,8(9):10355-10364
Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer treatment. In this study, we described a novel VEGFR2 inhibitor, xanthatin, which inhibits tumor angiogenesis and growth. The biochemical profiles of xanthatin were investigated using kinase assay, migration assay, tube formation, Matrigel plug assay, western blot, immunofluorescence and human tumor xenograft model. Xanthatin significantly inhibited growth, migration and tube formation of human umbilical vascular endothelial cell as well as inhibited vascular endothelial growth factor (VEGF)-stimulated angiogenesis. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator. Moreover, xanthatin directly inhibit proliferation of breast cancer cells MDA-MB-231. Oral administration of xanthatin could markedly inhibit human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that xanthatin inhibits angiogenesis and may be a promising anticancer drug candidate. 相似文献
122.
Fury MG Zahalsky A Wong R Venkatraman E Lis E Hann L Aliff T Gerald W Fleisher M Pfister DG 《Investigational new drugs》2007,25(2):165-172
Summary
Background: SU5416 (semaxanib) is a synthetic small molecule inhibitor of the tyrosine kinase domain of vascular endothelial growth factor
receptor 2 (VEGFR2). This Phase II study was conducted to determine the safety and efficacy of SU5416 in patients with recurrent
or metastatic head and neck cancers.
Patients and methods: This was an open label, single arm, Phase 2 study for patients who had received no more than 2 cytotoxic regimens. Thirty-five
patients received intravenous SU5416 (145 mg/m2) twice per week by intravenous catheter. Radiologic imaging for response assessment was planned at the conclusion of each
8 week cycle. Serum VEGF levels and power Doppler ultrasound tumor imaging were explored as potential surrogate markers for
SU5416 activity.
Results: Thirty-two patients had received prior radiotherapy, including 18 patients who received prior concurrent chemoradiotherapy.
Twelve patients had received prior chemotherapy in the recurrent disease setting. Thirty-one patients were evaluable for response.
There was one partial response and one minor response. The median number of 8-week cycles received was 1 (range 1–4). Median
overall survival was 6.25 months. The most common ≥ grade 3 toxicity was headache (31%). There was one fatal carotid artery
hemorrhage. Fatigue, nausea, and vomiting were common grade 1–2 adverse events. Power Doppler ultrasound demonstrated decreased
tumor vascularity in 5 of 7 patients.
Conclusions: Treatment with SU5416 in patients with head and neck cancers is feasible, but objective responses are rare. Studies evaluating
more potent anti-angiogenic agents in this disease are of interest.
Supported in Part by CTEP (NCI 79) U01-CA69913. 相似文献
123.
Michael Michael Peter Gibbs Robert Smith Alex Godwood Stuart Oliver Niall Tebbutt 《Investigational new drugs》2009,27(3):253-261
Summary
Background: Vandetanib (ZACTIMA™) is a once-daily oral inhibitor of vascular endothelial growth factor, epidermal growth factor and
RET receptor tyrosine kinases. The safety and tolerability of vandetanib plus mFOLFOX6 was investigated in patients with advanced
colorectal cancer (CRC). Methods: Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus
14-day treatment cycles of mFOLFOX6. Results: Seventeen patients received vandetanib 100 mg (n = 9) or 300 mg (n = 8) plus mFOLFOX6. The protocol definition of a tolerable dose (vandetanib-related dose-limiting toxicity [DLT] in less
than two patients) was met in both dose cohorts, with one DLT of diarrhoea reported in each. Overall, the most common adverse
events were diarrhoea, nausea and lethargy (all n = 11). There was no pharmacokinetic interaction between vandetanib and mFOLFOX6. Preliminary efficacy results included one
complete response and three confirmed partial responses. Conclusions: In patients with advanced CRC, once-daily vandetanib (100 or 300 mg) with mFOLFOX6 was generally well tolerated. 相似文献
124.
125.
Teri N. Kreisl Katharine A. McNeill Joohee Sul Fabio M. Iwamoto Joanna Shih Howard A. Fine 《Neuro-oncology》2012,14(12):1519-1526
Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor–2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma. 相似文献
126.
目的:观察藤黄酸对人结肠癌SW480细胞增殖和血管内皮细胞受体2(VEGFR2)表达的影响,探讨其可能抗肿瘤的作用机制。方法:以不同浓度的藤黄酸干预体外培养的人结肠癌细胞株SW480,分别于24、36、48h后,应用MTT法检测细胞增殖活性,流式细胞仪检测细胞周期分布和细胞凋亡率,Western-blot分析VEGFR2蛋白的变化。结果:藤黄酸对结肠癌细胞株SW480生长增殖具有明显抑制作用,其效应呈浓度和时间依赖性。流式细胞仪分析显示SW480细胞呈G2/M期阻滞;SW480细胞的凋亡率随藤黄酸浓度增加逐步上升。用不同浓度的藤黄酸处理SW480细胞株24h,VEGFR2蛋白的表达随药物浓度的增加而减少(P<0.01)。结论:藤黄酸能够明显抑制人结肠癌细胞株SW480的增殖,诱导SW480细胞发生G2/M期阻滞,其作用机制可能与抑制VEGFR2表达有关。 相似文献
127.
128.
Ziogas AC Gavalas NG Tsiatas M Tsitsilonis O Politi E Terpos E Rodolakis A Vlahos G Thomakos N Haidopoulos D Antsaklis A Dimopoulos MA Bamias A 《International journal of cancer. Journal international du cancer》2012,130(4):857-864
The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis is well characterized; nevertheless, it is also a key element in promoting tumor evasion of the immune system by downregulating dendritic cell maturation and thus T cell activation. We sought to investigate the possible direct effect of VEGF on T cell activation and through which type of VEGF receptor (VEGFR) it exerts this effect. Circulating T cells from healthy donors and ovarian cancer patients were expanded in cultures with anti-CD3 and IL-2 with or without VEGF for 14 days, and the number of T cells was assessed. Cultured T cells were also tested for their cytotoxic activity in a standard 4-hr (51) Cr-release assay, and the expression of VEGFRs 1, 2 and 3 was assayed by flow cytometry, immunocytochemistry and Western blotting. To assess the ability of activated T cells to secrete VEGF, levels in culture supernatants were measured by enzyme linked immunosorbent assay. The addition of VEGF in cultures significantly reduced T cell proliferation in a dose-dependent manner. Protein expression studies demonstrated that CD3(+) T cells express VEGFR-2 on their surface upon activation. Experiments with anti-VEGFR-2 antibodies showed that the direct suppressive effect of VEGF on T cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells and that activated T cells secrete VEGF in the culture environment. Overall, our study shows that T cells secret VEGF and expresses VEGFR-2 upon activation. VEGF directly suppresses T cell activation via VEGF receptor type 2. 相似文献
129.
目的:初步研究莪术醇促进血管生成的活性及作用机制,为临床用药提供依据.方法:采用斑马鱼生物模式,观察莪术醇对斑马鱼胚胎体节间血管生长、成鱼剪尾后血管再生和仔鱼切尾后组织再生情况.采用相对荧光定量PCR法检测仔鱼切尾后体内血管内皮生长因子(VEGFA)及受体(VEGFR2)基因的表达.结果:莪术醇能使斑马鱼胚胎体节间血管侧生出新的血管,使成鱼剪尾后血管再生加快,使仔鱼切尾后尾部再生加快.且莪术醇能提高仔鱼体内VEGFA及VEGFR2基因的表达量,促进仔鱼切尾后的尾部再生.结论:莪术醇能促进斑马鱼的血管生成,提高仔鱼切尾后体内VEGFA及VEGFR2基因的表达量,促进尾部再生. 相似文献
130.
Looking at the blood-brain barrier: Molecular anatomy and possible investigation approaches 总被引:1,自引:0,他引:1
Filipa Lourenço Cardoso 《Brain Research Reviews》2010,64(2):328-363
The blood-brain barrier (BBB) is a dynamic and complex interface between blood and the central nervous system that strictly controls the exchanges between the blood and brain compartments, therefore playing a key role in brain homeostasis and providing protection against many toxic compounds and pathogens. In this review, the unique properties of brain microvascular endothelial cells and intercellular junctions are examined. The specific interactions between endothelial cells and basement membrane as well as neighboring perivascular pericytes, glial cells and neurons, which altogether constitute the neurovascular unit and play an essential role in both health and function of the central nervous system, are also explored. Some relevant pathways across the endothelium, as well as mechanisms involved in the regulation of BBB permeability, and the emerging role of the BBB as a signaling interface are addressed as well. Furthermore, we summarize some of the experimental approaches that can be used to monitor BBB properties and function in a variety of conditions and have allowed recent advances in BBB knowledge. Elucidation of the molecular anatomy and dynamics of the BBB is an essential step for the development of new strategies directed to maintain or restore BBB integrity and barrier function and ultimately preserve the delicate interstitial brain environment. 相似文献