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111.
Youzhi Xu Hongjun Lin Nana Meng Wenjie Lu Guobo Li Yuanyuan Han Xiaoyun Dai Yong Xia Xiangrong Song Shengyong Yang Yuquan Wei Luoting Yu Yinglan Zhao 《British journal of pharmacology》2013,169(8):1766-1780
Background and Purpose
Targeted chemotherapy using small-molecule inhibitors of angiogenesis and proliferation is a promising strategy for cancer therapy.Experimental Approach
YL529 was developed via computer-aided drug design, de novo synthesis and high-throughput screening. The biochemical, pharmacodynamic and toxicological profiles of YL529 were investigated using kinase and cell viability assays, a mouse tumour cell-containing alginate bead model, a zebrafish angiogenesis model and several human tumour xenograft models in athymic mice.Key Results
In vitro, YL529 selectively inhibited the activities of VEGFR2/VEGFR3 and serine/threonine kinase RAF kinase. YL529 inhibited VEGF165-induced phosphorylation of VEGFR2, as well as the proliferation, migration, invasion and tube formation of human umbilical vascular endothelial cells. It also significantly blocked vascular formation and angiogenesis in the zebrafish model. Moreover, YL529 strongly attenuated the proliferation of A549 cells by disrupting the RAF/mitogen-activated protein (MAP) or extracellular signal-regulated kinase (Erk) kinase (MEK) kinase kinase/MAPK pathway. Oral administration of YL529 (37.5–150 mg−1·kg−1·day−1) to nude mice bearing established tumour xenografts significantly prevented the growth (60–80%) of A549, SPC-A1, A375, OS-RC-2 and HCT116 tumours without detectable toxicity. YL529 markedly reduced microvessel density and increased tumour cell apoptosis in the tumours formed in mice inoculated with the lung cancer cells, SPC-A1 and A549, and the colon carcinoma cells, HCT116.Conclusions and Implications
YL529, an orally active multikinase inhibitor, shows therapeutic potential for solid tumours, and warrants further investigation as a possible anticancer agent. 相似文献112.
Experimental inhibition of corneal neovascularization by endostatin gene transfection in vivo 总被引:6,自引:0,他引:6
Objective To investigate endostatin gene therapy of rat corneal neovascularization induced by acid cauterization. Methods pBlast-hEndostatin and pBlast-Mcs were identified by digestion with Nhe Ⅰand Sal Ⅰ, by PCR reaction, by sequence, and then by alignment of PCR products with the geneBank using NCBIBLAST software. They were then purified with QIAGEN Endofree plasmid maxi kit. Rat corneal neovascularization models were made with 75% AgNO3 and 25% KNO3 cauterization. The treatment method was subconjunctive injection of the pBlast-hEndostatin with the control of pBlast-Mcs. Results pBlast-hEndostatin was found to contain the human endostatin gene. The rat corneal neovascularization induced by acid cauterization was significantly suppressed after subconjunctive injection of the pBlast-hEndostatin with inhibition rates of 37%, 40.2%, and 42.8% respectively on the sixth, tenth, and fifteenth day. The inhibition rate for the density of corneal neovascularization was 40%. However, no inhibition effect on the length of the neovascularization and corneal inflammatory cells was observed. Corneal neovascularization areas were positively correlated with edema and corneal opacity.Conclusions The plasmid of pBlast-hEndostatin contained the human endostatin gene. The rat corneal neovascularization induced by acid cauterization can be partially inhibited by subconjunctive injection of the pBlast-hEndostatin mediated by liposomes. Endostatin produced by transfected fibroblast cells directly inhibits corneal neovascularization. This is not caused by inflammatory reaction inhibition. 相似文献
113.
Thalidomide as an Anti-angiogenic Agent in Relapsed Gliomas 总被引:2,自引:0,他引:2
BACKGROUND: Thalidomide (alpha-phthalimidoglutarimide), a synthetic sedative drug, has anti-angiogenic properties due to inhibition of growth-factor mediated neovascularisation and has been shown to inhibit tumour growth in experimental solid tumour models. AIM: To assess response of recurrent malignant gliomas to thalidomide. METHODS: Eighteen patients with recurrent gliomas were enrolled to an open, non-randomised phase II trial between October 1997 and December 1999. All patients had failed following treatment with radiotherapy and chemotherapy with PCV and/or temozolomide regimens. Eleven patients had high-grade gliomas de novo and 7 high-grade gliomas following transformation of low-grade gliomas. Thalidomide was prescribed at 100 mg/day p.o. continuously. Response was assessed at 4-weekly intervals. Disease progression was defined as neurological deterioration and/or radiological evidence of increased tumour size. Treatment was discontinued at the time of disease progression, or if toxicity occurred, or at patients' request. RESULTS: Thalidomide was prescribed for a median of 42 days (range 7-244). Treatment was discontinued due to toxicity (peripheral sensory neuropathy) in 1 patient. Six patients died before response could be fully assessed and are classified as non-responders. Of 12 who continued treatment for more than 4 weeks, 1 patient had clinical and radiological response (PR), 2 patients had stable disease for 2 and 4 months respectively and 9 patients had disease progression. The median survival from the start of thalidomide was 2.5 months. CONCLUSION: The efficacy of thalidomide in terms of response in recurrent gliomas is low, with a partial response rate of only 6%. Future studies should investigate thalidomide in combination with other agents and at an earlier stage of disease. Methods to assess anti-angiogenic properties such as changes in tumour vasculature could be employed as initial surrogate end-points in the investigation of efficacy. 相似文献
114.
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。 相似文献
115.
116.
Recent advances in angiogenesis,anti-angiogenesis and vascular targeting 总被引:10,自引:0,他引:10
Angiogenesis, the development of new blood vessels, has become a major focus of research. This has been stimulated by the therapeutic opportunities offered by the ability to manipulate the vasculature in pathologies such as cancer. Here, we present an overview of recent advances in angiogenesis. Especially noteworthy is the large volume of information from developmental studies, particularly those that involve transgenic and gene knockout mice. We also discuss the increasing repertoire of drugs with which to manipulate angiogenesis and new endothelial-specific genes with which to target the vasculature. 相似文献
117.
Author to whom correspondence should be sent; present address: Department of Mathematics and Computer Science, University of Dundee, Dundee, DD1 4HN, UK There is a very strong link between the vascularization of atumour and the spread of the disease, both locally and to distantsites (Gimbrone et al., 1974, J. Natl. Cancer Inst. 52, 41327;Muthukkaruppan et al, 1982, J. Natl. Cancer Inst. 69, 699704;Ellis & Fiddler, 1995, Lancet 346, 3889). A tumourbecomes vascularized by a process known as angiogenesis. Tumourangiogenesis is initiated by the release of diffusible substancesby the tumour, whereby neighbouring capillary vessels are stimulatedto grow and eventually penetrate the tumour. Anti-angiogenesishas been proposed as a potential strategy for the treatmentof cancer (Folkman, 1995, Nature Med. 1, 2131; Harriset al, 1996, Breast Cancer Res. Treat. 38, 97108). Inthis paper, a mathematical model of the development of the tumourvasculature is presented. By suitable manipulation of the modelparameters, we simulate various anti-angiogenesis strategiesand we examine the roles that haptotaxis and chemotaxis mayplay during the growth of the neovasculature. The model is simulatedin two space dimensions (on a square domain) so that it is,in theory, experimentally reproducible and any predictions ofthe model can therefore be tested. 相似文献
118.
目的:观察程序性细胞死亡因子1 (programmed cell death 1,PD-1)免疫治疗联合贝伐单抗进行抗血管生成双靶治疗Ⅳ期肺腺癌的疗效,并分析其对细胞免疫功能、短期预后和不良反应的影响.方法:选取成都大学附属医院2018年12月至2020年8月收治的Ⅳ期肺腺癌患者67例,按照治疗方式不同分为对照组(n=33)和联合组(n=34),对照组予以化疗+PD-1抑制剂治疗,联合组予以化疗+PD-1抑制剂+贝伐单抗治疗,比较2组患者近期治疗疗效、治疗前后细胞免疫功能、卡氏功能状态(Kamofsky performance status,KPS)评分变化情况、不良反应及无进展生存期.结果:联合组患者治疗总有效率和疾病控制率分别为29.41%和79.41%,显著高于对照组的9.09%和54.55%(P<0.05);治疗后,联合组患者CD3+、CD4+、CD4+/CD8+显著高于对照组(P<0.05),CD8+与对照组患者比较无统计学差异(P>0.05);联合组患者KPS评分增加稳定率为73.53%,显著高于对照组患者的45.45% (P<0.05);联合组患者骨髓抑制、消化道反应、血液毒性、肝肾功能损害及周围神经毒性不良反应发生率与对照组患者比较,差异无统计学意义(P>0.05);联合组患者中位无进展生存期为9.73个月,对照组患者中位无进展生存期为6.05个月,差异有统计学意义(P<0.05).结论:PD-1免疫治疗联合贝伐单抗进行抗血管生成双靶治疗Ⅳ期肺腺癌,可明显提高近期治疗疗效,改善患者免疫功能,提高其生存质量,延长其无进展生存时间. 相似文献
119.
胰腺癌基质在肿瘤进展、侵袭、转移和治疗抵抗中扮演着重要角色,单纯的靶向肿瘤细胞治疗策略已无法满足延长患者生存期的临床治疗需求。越来越多的研究着眼于靶向胰腺癌基质治疗与化疗、放疗和免疫疗法联合用药方案的开发。胰腺癌复杂的基质成分、互相串扰的信号通路和畸形增生的新生血管给靶向药物的研究开发带来了巨大挑战的同时也提供了相应的机遇。本文主要从细胞外基质(extracellular matrix,ECM)、肿瘤相关成纤维细胞(cancer associated fibroblasts,CAFs)和血管3个方面,综述了近期靶向胰腺癌基质治疗策略研究进展并加以分析讨论,以期为胰腺癌的靶向治疗提供新思路。 相似文献
120.
非小细胞肺癌(non-small cell lung cancer,NSCLC)的增殖、浸润、转移都需要新生血管的支持,抗血管生成治疗已成为一种重要治疗手段。血管内皮生长因子(vascular endothelial growth factor,VEGF)作为关键的促血管生成因子,是目前NSCLC抗血管生成治疗药物的主要靶点。这些药物主要包括以VEGF或其受体VEGFR为靶点的单克隆抗体,及阻断VEGFR下游信号通路传导的小分子酪氨酸激酶抑制剂(VEGFR-TKI)两类。目前有两种抗血管生成单克隆抗体,贝伐单抗及雷莫卢单抗,被批准联合化疗一线或二线治疗原位进展或转移的NSCLC。多种VEGFR-TKI治疗NSCLC的临床试验均以失败告终,目前仅有安罗替尼在我国被批准用于NSCLC的三线治疗,而尼达尼布联合化疗在二线治疗中也显示了良好的生存获益。本篇综述我们将回顾总结抗血管生成药物单药或与其他抗肿瘤药物联用成功应用于NSCLC治疗的临床研究数据。 相似文献