PET Imaging of Hypoxia with EF5

使用 EF5 进行缺氧 PET 成像

• 批准号: 7541777
• 负责人: CAMERON J KOCH
• 金额: $ 34.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541777
• 关键词: Affect; Angiogenesis Inhibitors; Animal Model; Animals; Antibodies; Binding; Biochemistry; Biological Assay; Biopsy; Blood flow; Cells; Clinical Research; Data; Detection; Development; Drug Kinetics; EF5; Electrodes; Engineering; Face; Finland; Fluorescence Microscopy; Fluorides; Fluorine; Gases; Genes; Genetic; Goals; Grant; Heterogeneity; Homologous Gene; Human; Hypoxia; Image; In Situ; Individual; Institution; Intensity-Modulated Radiotherapy; Intercellular Fluid; Label; Laboratories; Lead; Location; Malignant Neoplasms; Measures; Metals; Methods; Modality; Modeling; Molecular Biology; Monitor; Nature; Needles; Normal tissue morphology; Nude Rats; Oxygen; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Positron-Emission Tomography; Prediction of Radiation Response; Property; Proteins; Radiation; Radioactive; Rattus; Research; Research Personnel; Resistance; Resolution; Role; Signal Transduction; Spatial Distribution; Techniques; Technology; Technology Transfer; Testing; Tissue Sample; Tissues; Validation; Variant; Vascular blood supply; Xenograft procedure; antiangiogenesis therapy; azomycin; base; cancer therapy; clinically relevant; copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); driving force; gliosarcoma; innovation; interest; method development; pressure; programs; proton beam; radiation resistance; resistance factors; response; sarcoma; success; time interval; tissue oxygenation; tumor; uptake; Affect; Angiogenesis Inhibitors; Animal Model; Animals; Antibodies; Binding; Biochemistry; Biological Assay; Biopsy; Blood flow; Cells; Clinical Research; Data; Detection; Development; Drug Kinetics; EF5; Electrodes; Engineering; Face; Finland; Fluorescence Microscopy; Fluorides; Fluorine; Gases; Genes; Genetic; Goals; Grant; Heterogeneity; Homologous Gene; Human; Hypoxia; Image; In Situ; Individual; Institution; Intensity-Modulated Radiotherapy; Intercellular Fluid; Label; Laboratories; Lead; Location; Malignant Neoplasms; Measures; Metals; Methods; Modality; Modeling; Molecular Biology; Monitor; Nature; Needles; Normal tissue morphology; Nude Rats; Oxygen; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Positron-Emission Tomography; Prediction of Radiation Response; Property; Proteins; Radiation; Radioactive; Rattus; Research; Research Personnel; Resistance; Resolution; Role; Signal Transduction; Spatial Distribution; Techniques; Technology; Technology Transfer; Testing; Tissue Sample; Tissues; Validation; Variant; Vascular blood supply; Xenograft procedure; antiangiogenesis therapy; azomycin; base; cancer therapy; clinically relevant; copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); driving force; gliosarcoma; innovation; interest; method development; pressure; programs; proton beam; radiation resistance; resistance factors; response; sarcoma; success; time interval; tissue oxygenation; tumor; uptake

DESCRIPTION (provided by applicant): There are many clinical studies directly demonstrating the importance of hypoxia in limiting the response to essentially all forms of cancer therapy. Additionally, hypoxia is thought to affect the very nature of cancer, with hypoxic tumors being more susceptible to genetic instability and aggressive phenotypes. At present, it is not known whether hypoxia is simply associated with aggressive tumors, or whether it is the driving force. There has been a great interest in the development of methods to image clinically relevant tumor hypoxia by non-invasive means. In this Application we will employ a 2-nitroimidazole hypoxia marker, EF5, for this purpose. EF5 is unique because its oxygen-dependent bioreduction can be studied in two distinct ways: first; highly specific antibodies can be used for quantitative immunohistochemical detection at sub-cellular resolution (e.g. fluorescence microscopy of tissue sections or flow cytometric analysis) and secondly; non-invasive imaging using F-18-1abeled drug. Both methods have been shown to correlate with individual-tumor radiation-response prediction in the 9L gliosarcoma rat-tumor-model. Using this model, three hypotheses will be tested (a fourth will employ the HTIOB0 human sarcoma xenograft): The first aim will test the hypothesis that moderate to high concentrations of hypoxia markers are necessary to promote optimal prediction of tissue hypoxia. This represents a continuation of our prior grant and requires the engineering of an innovative method (developed by Dr. Olof Solin in Finland) to produce high specific activity fluorine gas (not possible with normal techniques). The technology developed in this aim will benefit planned human studies, and allow new methods for labeling compounds with radioactive fluorine. The second Aim will compare the now validated radiation response prediction of EF5 with two other clinically relevant techniques: uptake of labeled Cu-ATSM and interstitial fluid pressure. The goal in this aim is to assess whether the various predictive assays are truly monitoring hypoxia, or other relevant resistance factors. The 3rd Aim will test the clinically relevant hypothesis that F-18-EF5 imaging can detect intra-tumoral changes in radiation resistance caused by heterogeneity in the spatial distribution of hypoxia. Success of this Aim could lead to important new uses of therapies such as IMRT and proton beams which can be directed to spatial locations of one cc or so. Our final Aim, to be studied in the HT1080 human sarcoma xenograft, will test the hypothesis that F-18-EF5 imaging can monitor microenvironmental changes caused by antivascular and antiangiogenic therapies. In summary, the aims of this grant will extend and advance our overall laboratory interest in quantifying the degree and extent of clinically relevant hypoxia in the tumor microenvironment.

描述（由申请人提供）： 有许多临床研究直接表明缺氧在限制对所有形式的癌症治疗的反应中的重要性。此外，缺氧被认为会影响癌症的本质，缺氧性肿瘤更容易受到遗传不稳定性和攻击性表型的影响。目前，尚不清楚缺氧是否仅仅与侵袭性肿瘤相关，或者是驱动力。人们对通过非侵入性手段对临床相关的肿瘤缺氧的方法的发展产生了极大的兴趣。在此应用中，我们将使用2-硝基咪唑低氧标记EF5为此目的。 EF5之所以独特，是因为它的氧依赖性生物补充能够以两种不同的方式研究：首先；高度特异性的抗体可用于下细胞分辨率（例如，组织切片的荧光显微镜或流式细胞仪分析），用于定量免疫组织化学检测，其次；使用F-18-1档的药物进行非侵入性成像。两种方法均显示与9L胶质瘤大鼠肿瘤模型中的个体肿瘤辐射反应预测相关。使用该模型，将检验三个假设（第四个将采用HTIOB0人类肉瘤异种移植物）：第一个目标将检验以下假设：中度至高浓度的缺氧标志物是为了促进组织缺氧的最佳预测所必需的。这代表了我们先前的赠款的延续，需要一种创新方法的工程（由芬兰的Olof Solin博士开发），以产生高特异性活动氟气体（使用正常技术不可能）。在此目标中开发的技术将使计划中的人类研究受益，并允许使用放射性氟标记化合物的新方法。第二个目标将将EF5的现在验证的辐射响应预测与其他两种临床相关技术进行比较：对标记的Cu-ATSM和间质流体压力的吸收。此目的的目的是评估各种预测性测定是真正监测缺氧还是其他相关抗性因素。第三个目标将检验临床上相关的假设，即F-18-EF5成像可以检测到缺氧空间分布中异质性引起的辐射抗性的肿瘤内变化。该目标的成功可能会导致诸如IMRT和质子梁等疗法的重要新用途，这些疗法可将其定向到一个CC左右的空间位置。我们的最终目标将在HT1080人类肉瘤异种移植物中进行研究，将检验以下假设：F-18-EF5成像可以监测由抗血管和抗血管生成疗法引起的微环境变化。总而言之，这笔赠款的目的将扩展和提高我们在量化肿瘤微环境中临床相关缺氧程度和程度的总体实验室利益。