In situ detection of apoptosis in tumor endothelial cells

原位检测肿瘤内皮细胞凋亡

• 批准号: 6563959
• 负责人: David J. McConkey
• 金额: $ 29.68万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563959
• 关键词: angiogenesis inhibitors; apoptosis; athymic mouse; biomarker; blood flow measurement; colon neoplasms; cooperative study; growth factor receptors; human subject; human therapy evaluation; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplastic growth; pancreas neoplasms; patient oriented research; prostate neoplasms; radiography; terminal nick end labeling; vascular endothelial growth factors; vascular endothelium

Description: (provided by applicant) Agents that target tumor vasculature have tremendous potential as anti-cancer therapies because they do not appear to induce drug resistance. However, these agents are cytostatic rather than cytotoxic, which poses a unique set of problems for the evaluation of drug efficacy because classical measures of tumor "response" may not be valid. It will be especially important to identify their biological mechanisms of action and to develop new methods to detect these effects in in primary patient tissue specimens. To this end, we have developed a technique that allows for the detection of dying tumor endothelial cells, and our preliminary results strongly suggest that antiangiogenic agents induce apoptosis in tumor endothelial cells. The overall goal of the present studies is to determine whether endothelial cell apoptosis is a sensitive marker or efficacy in tumors treated with anti-angiogenic therapies that can distinguish patients who respond to these drugs from those who do not. To this end, we propose to: (1) Define the role of specific "survival" pathways in the maintenance of endothelial cell viability in vitro. Cells will be exposed to growth factor withdrawal or VEGF receptor antagonists, and effects on signaling pathways previously implicated in cell survival (i.e. AKT) will be evaluated. We will also isolate mRNA from these cells and analyze changes in apoptosis-associated gene expression following VEGF withdrawal. (2) Determine the role of endothelial cell apoptosis in orthotopic tumor models. Nude mice bearing human pancreatic, colon, or prostate tumors will be treated with investigational agents, and effects on tumor endothelial cell apoptosis will be measured by CD31/TUNEL staining. (3) Characterize the role of endothelial cell apoptosis in the effects of antiangiogenic therapies in patients. Levels of endothelial cell apoptosis in patients treated with anti-angiogenic agents will be correlated with tumor blood flow changes and radiographic measurements of response. These studies will allow us to rapidly determine whether tumor endothelial cell apoptosis can be used as a surrogate for clinical response in patients treated with this class of novel anti-cancer agents.

说明：（申请人提供） 针对肿瘤血管系统的药物具有巨大的抗癌潜力 疗法，因为它们似乎不会诱导耐药性。然而， 这些药物是细胞抑制性的而不是细胞毒性的，这构成了一组独特的 药物疗效评价中存在的问题是因为经典的测量方法 肿瘤“反应”可能无效。这将尤其重要 确定其生物学作用机制并开发新方法 在原发性患者组织标本中检测这些影响。为此，我们 开发了一种可以检测垂死肿瘤的技术 内皮细胞，我们的初步结果强烈表明抗血管生成 药物诱导肿瘤内皮细胞凋亡。整体 本研究的目的是确定内皮细胞凋亡是否 是抗血管生成治疗肿瘤的敏感标志物或功效 可以区分对这些药物有反应的患者和那些对这些药物有反应的患者的疗法 谁不。为此，我们建议：（1）明确具体角色 体外维持内皮细胞活力的“生存”途径。 细胞将暴露于生长因子撤除或 VEGF 受体 拮抗剂以及对先前与细胞有关的信号通路的影响 将评估生存率（即 AKT）。我们还将从这些中分离出 mRNA 细胞并分析细胞凋亡相关基因表达的变化 VEGF 戒断。 (2)确定内皮细胞凋亡的作用 原位肿瘤模型。携带人类胰腺、结肠或 前列腺肿瘤将用研究药物进行治疗，并对其产生影响 通过CD31/TUNEL染色测量肿瘤内皮细胞凋亡。 (3) 表征内皮细胞凋亡在抗血管生成作用中的作用 对患者进行治疗。内皮细胞凋亡水平 接受抗血管生成药物治疗的患者将与肿瘤相关 血流变化和反应的放射线测量。这些研究 将使我们能够快速确定肿瘤内皮细胞是否发生凋亡 可用作接受该治疗的患者临床反应的替代指标 一类新型抗癌药物。