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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 在这个项目中，我们将使用两种单独或组合使用两种新型方法来测试[18F] EF5-PET成像的值，以检测肿瘤缺氧的减少。两种方法均基于葡萄糖作为低氧细胞的能源的独家需求。我们先前报道说，抑制转录因子HIF-1可以阻止糖酵解酶的合成，从而防止使用葡萄糖低氧肿瘤细胞。慢性HIF-1抑制导致低氧细胞坏死。我们最近发现的第二种方法是基于实体瘤含有氧化和低氧区域的混合物的事实。低氧肿瘤细胞主要利用葡萄糖通过糖酵解和释放乳酸来产生能量。在存在氧气的情况下，某些肿瘤能够通过单羧酸盐转运蛋白MCT1进口乳酸，并氧化液以恢复ATP。在这种情况下，乳酸是呼吸过程中葡萄糖的首选底物。 MCT1的抑制延迟肿瘤的生长，并增加了由于氧化性肿瘤细胞从乳酸氧化转换为葡萄糖分解代谢而提高其对放射疗法的敏感性。该转换导致低氧细胞因葡萄糖饥饿而死亡。在这项研究中，我们将使用缺氧成像剂[18F] EF5作为缺氧的定量PET示踪剂，以抑制鞋底转运（MCT1）和HIF-1。在抑制鞋底转运（MCT1）和HIF-1。的固体瘤中选择性缺氧细胞杀死的效率。我们将[18F] EF5 PET信号与EF5结合的免疫组织化学分析进行比较。该项目的目的是结合缺氧成像剂[18F] EF5建立PET成像技术的潜力，以非侵入性的方式监测缺氧细胞杀伤疗法的成功。