New Molecular Approaches to Inhibit Glioma Angiogenesis

抑制神经胶质瘤血管生成的新分子方法

• 批准号: 6633959
• 负责人: ELIZABETH W. NEWCOMB
• 金额: $ 25.99万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633959
• 关键词: angiogenesis; angiogenesis inhibitors; antisense nucleic acid; apoptosis; athymic mouse; cyclins; enzyme linked immunosorbent assay; flavopiridol; gene induction /repression; glioma; hypoxia; magnetic resonance imaging; neoplasm /cancer genetics; neoplastic growth; oligonucleotides; p53 gene /protein; protein kinase; protooncogene; transcription factor; vascular endothelial growth factors

DESCRIPTION: (Applicant's Abstract) Glioblastoma (GBM) is one of the most chemoresistant and angiogenic types of tumors known. Several treatments have failed in altering survivals beyond 12 months of diagnosis. The broad objective of this proposal will be to investigate new approaches to inhibit angiogenesis in GBM using different animal models. Hypoxia-inducible factor l alpha (HIF-1a) becomes up regulated in hypoxic conditions and leads to angiogenesis via vascular endothelial growth factor (VEGF) expression. Normally wildtype p53 promotes MDM2-mediated ubiquitination and proteosomal degradation of the HIF-la protein, thus limiting VEGF-induced angiogenesis. Loss of wildtype p53 function has been associated with neovascularization and growth of xenografts in nude mice. We hypothesize that overexpression of MDM2 (seen in more than 50 percent of GBM), a gene directly regulated by p53 and also linked with resistance to chemotherapy in human GBM cell lines, could lead to the sequestration of p53 in p53-MDM2 complexes preventing the normal p53 MDM2-mediated degradation of HIF-1a. Here we show flavopiridol, a novel protein kinase inhibitor with reported antiangiogenic activity, down regulates HIF-1a expression in glioma cell lines in vitro, thus providing one mechanism for its antiangiogenic activity. The proposed studies will evaluate MDM2 antisense treatment with and without flavopiridol to promote down regulation of MDM2 expression in glioma cell lines and xenografts, up regulation of p53-mediated responses and down regulation of HIF-1a/VEGF expression to decrease angiogenic-signaling. This will be accomplished by 1) Use of in vitro studies to optimize MDM2 antisense and drug treatment conditions that promote p53 function and/or decrease HIF-la/VEGF expression, respectively, under hypoxic growth conditions. 2) Use of the murine glioma GL261 intracranial model of angiogenesis to determine the capacity of flavopiridol to decrease HIF-1a/VEGF expression and antiangiogenic activity in hypoxic conditions. 3,4) Use of nude mice xenografts both subcutaneously and intracranially to determine the in vivo activity of MDM2 antisense treatment with and without flavopiridol to inhibit angiogenesis and tumor growth in hypoxic conditions.

描述：（申请人摘要）胶质母细胞瘤（GBM）是最常见的一种 已知的化学抗性和血管生成类型的肿瘤。几种治疗方法都有 未能改变诊断后 12 个月后的生存率。广泛的目标 该提案的目的是研究抑制血管生成的新方法 在 GBM 中使用不同的动物模型。缺氧诱导因子 l α (HIF-1a) 在缺氧条件下上调并通过以下方式导致血管生成 血管内皮生长因子（VEGF）表达。通常为野生型 p53 促进 MDM2 介导的 HIF-la 泛素化和蛋白体降解 蛋白，从而限制 VEGF 诱导的血管生成。野生型 p53 功能丧失 与裸体内异种移植物的新血管形成和生长有关 老鼠。我们假设 MDM2 的过度表达（见于超过 50%） GBM），一个由 p53 直接调控的基因，也与耐药性相关 人类 GBM 细胞系中的化疗可能导致 p53 被隔离在 p53-MDM2 复合物阻止 p53 MDM2 介导的正常降解 HIF-1a。在这里，我们展示了黄酮吡醇，一种新型蛋白激酶抑制剂 据报道具有抗血管生成活性，下调神经胶质瘤中 HIF-1a 的表达 体外细胞系，从而为其抗血管生成提供了一种机制 活动。拟议的研究将评估 MDM2 反义治疗和 不含黄吡醇促进胶质瘤中 MDM2 表达下调 细胞系和异种移植物，上调 p53 介导的反应并下调 调节 HIF-1a/VEGF 表达以减少血管生成信号传导。这 将通过以下方式完成： 1) 使用体外研究来优化 MDM2 反义 以及促进 p53 功能和/或减少的药物治疗条件 在低氧生长条件下分别表达HIF-1α/VEGF。 2）使用 鼠神经胶质瘤 GL261 颅内血管生成模型的测定 黄吡醇降低 HIF-1a/VEGF 表达和抗血管生成的能力 缺氧条件下的活动。 3,4) 使用裸鼠异种移植物 皮下和颅内测定 MDM2 的体内活性 使用或不使用黄吡醇的反义治疗可抑制血管生成和 肿瘤在缺氧条件下生长。

项目成果

Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: a novel function for an old drug.

• DOI: 10.3892/ijo.28.5.1121
• 发表时间: 2006-05
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: E. Newcomb;Yevgeniy Lukyanov;Tona Schnee;M. Ali;L. Lan;D. Zagzag

Flavopiridol Induces Mitochondrial-Mediated Apoptosis in Murine Glioma GL261 Cells via Release of Cytochrome c and Apoptosis Inducing Factor

• DOI: 10.4161/cc.2.3.357
• 发表时间: 2003-01-01
• 期刊: CELL CYCLE
• 影响因子: 4.3
• 作者: Newcomb, Elizabeth W.;Tamasdan, Cristina;Zagzag, David
• 通讯作者: Zagzag, David

Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway.

Flavopiridol 通过不依赖 caspase 的途径诱导神经胶质瘤细胞系凋亡，不依赖于视网膜母细胞瘤和 p53 肿瘤抑制途径的改变。

• 发表时间: 2003
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Alonso,Michelle;Tamasdan,Cristina;Miller,DouglasC;Newcomb,ElizabethW
• 通讯作者: Newcomb,ElizabethW

Expression of p27KIP1 in human gliomas: relationship between tumor grade, proliferation index, and patient survival.

p27KIP1 在人神经胶质瘤中的表达：肿瘤分级、增殖指数和患者生存之间的关系。

• DOI: 10.1053/hupa.2003.54
• 发表时间: 2003
• 期刊: Human pathology.
• 作者: Zagzag,David;Blanco,Cy;Friedlander,DavidR;Miller,DouglasC;Newcomb,ElizabethW
• 通讯作者: Newcomb,ElizabethW