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：（申请人的摘要）胶质母细胞瘤（GBM）是最多的 已知的化学耐药性和血管生成类型。有几种治疗方法 在诊断12个月以上的生存改变无法改变。广泛的目标 该提案将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。低氧诱导因子Lα（HIF-1A） 在低氧条件下受到调节，并导致通过 血管内皮生长因子（VEGF）表达。通常是野生型p53 促进MDM2介导的HIF-LA的泛素化和蛋白质体降解 蛋白质，从而限制VEGF诱导的血管生成。 WildType P53功能的损失 与裸体中的新生血管形成和异种移植物的生长有关 老鼠。我们假设MDM2的过表达（可在超过50％ GBM），一种直接调节p53的基因，也与对 人类GBM细胞系中的化学疗法可能导致p53的隔离 p53-MDM2复合物可防止正常的p53 MDM2介导的降解 HIF-1A。在这里，我们展示了黄酮葡萄夫醇，这是一种新型蛋白激酶抑制剂， 报道的抗血管生成活性，下调了神经胶质瘤中HIF-1A的表达 体外细胞系，因此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的反义治疗和 没有黄酮属醇可促进神经胶质瘤中MDM2表达的调节 细胞系和异种移植物，p53介导的反应的调节和向下调节 调节HIF-1A/VEGF表达以减少血管生成信号。这 将通过1）使用体外研究来优化MDM2反义 促进p53功能和/或降低的药物治疗条件 HIF-LA/VEGF表达分别在低氧生长条件下。 2）使用 鼠神经胶质瘤GL261颅内模型的血管生成，以确定 黄叶肽降低HIF-1A/VEGF表达和抗血管生成的能力 低氧条件下的活性。 3,4）使用裸鼠异种移植 皮下和颅内以确定MDM2的体内活性 反义治疗有或没有黄酮病毒以抑制血管生成和 低氧条件下的肿瘤生长。

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

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

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