EVALUATION [18F]EF5 AS PET AGENT TO MONITOR ANTI-HYPOXIC TUMOR THERAPY

评估 [18F]EF5 作为宠物药物来监测抗缺氧肿瘤治疗

• 批准号: 8171602
• 负责人: SATISH CHITNENI
• 金额: $ 0.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171602
• 关键词: Binding; Catabolism; Cells; Cessation of life; Chronic; Computer Retrieval of Information on Scientific Projects Database; EF5; Energy-Generating Resources; Enzymes; Evaluation; Funding; Glucose; Glycolysis; Goals; Grant; Hypoxia; Image; Imaging Techniques; Institution; Monitor; Necrosis; Oxygen; Positron-Emission Tomography; Process; Production; Radiation therapy; Reporting; Research; Research Personnel; Resources; Respiration; Signal Transduction; Solid Neoplasm; Source; Starvation; Testing; Tracer; United States National Institutes of Health; base; cell killing; neoplastic cell; novel strategies; oxidation; prevent; success; transcription factor; tumor; tumor growth

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this project, we will test the value of [18F]EF5-PET imaging to detect reduction in tumor hypoxia, using two novel approaches, alone or in combination. Both approaches are based on the exclusive requirement of glucose as an energy source for hypoxic cells. We previously reported that inhibition of the transcription factor, HIF-1, blocks the synthesis of glycolytic enzymes, thereby preventing hypoxic tumor cells from using glucose. Chronic HIF-1 inhibition led to hypoxic cell necrosis. The second approach that we have recently discovered is based on the fact that solid tumors contain a mixture of oxygenated and hypoxic regions. Hypoxic tumor cells primarily use glucose for energy production by glycolysis and release lactate. In the presence of oxygen, certain tumors are able to import lactate via the monocarboxylate transporter MCT1, and oxidize it to recover ATP. In this setting, lactate is a preferred substrate to glucose in the respiration process. Inhibition of MCT1 delays tumor growth and increases their sensitivity for radiotherapy due to the switch-over of oxidative tumor cells from lactate oxidation to glucose catabolism. This switch leads to death of hypoxic cells from glucose starvation. In this study we will monitor the efficiency of selective hypoxic cell kill in solid tumors upon inhibition of lactate transport (MCT1) and HIF-1¿, using the hypoxia imaging agent [18F]EF5 as a quantitative PET tracer of hypoxia. We will compare the [18F]EF5 PET signal with the immunohistochemical analysis of EF5 binding. The goal of this project is to establish the potential of PET imaging technique, in combination with hypoxia imaging agent [18F]EF5, to monitor the success of hypoxia cell kill therapy in a non invasive manner.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 在该项目中，我们将单独或组合使用两种新方法来测试 [18F]EF5-PET 成像在检测肿瘤缺氧减少方面的价值，这两种方法都基于葡萄糖作为缺氧能源的唯一需求。我们之前报道过，抑制转录因子 HIF-1 会阻止糖酵解酶的合成，从而防止缺氧肿瘤细胞利用葡萄糖，慢性 HIF-1 抑制会导致缺氧细胞坏死。我们最近发现的第二种方法是基于以下事实：实体瘤包含含氧区域和缺氧区域的混合物，缺氧肿瘤细胞主要利用葡萄糖通过糖酵解产生能量，并在有氧的情况下释放乳酸。通过单羧酸转运蛋白 MCT1 输入乳酸，并将其氧化以恢复 ATP 在这种情况下，乳酸是呼吸过程中葡萄糖的首选底物。抑制 MCT1 可以延缓肿瘤生长。由于氧化肿瘤细胞从乳酸氧化转变为葡萄糖分解代谢，这种转变导致缺氧细胞因葡萄糖饥饿而死亡。在这项研究中，我们将监测实体瘤中选择性缺氧细胞杀死的效率。抑制乳酸转运 (MCT1) 和 HIF-1¿ ，使用缺氧显像剂 [18F]EF5 作为缺氧的定量 PET 示踪剂 我们将比较 [18F]EF5 PET 信号与 EF5 结合的免疫组织化学分析 该项目的目标是确定 PET 成像技术的潜力。 ，与缺氧显像剂[18F]EF5结合，以非侵入性方式监测缺氧细胞杀伤治疗的成功。