Nuclear Magnetic Resonance Imaging of Tumor Hypoxia

治疗策略是根据危险因素分层的；分层到不同的预后组的目标是 设计基于风险的治疗策略。长期存活率是由“风险因素”决定的 预后参数，如局部控制的概率和发生全身性或转移的风险 疾病。肿瘤缺氧对转移风险和侵袭性局部疾病均有预测作用。一个 测量缺氧的非侵入性分析将提供局部肿瘤的预后信息 用于开发基于风险的治疗的侵袭性和转移风险，以及用于监测 氧合治疗，可能会影响进一步的治疗。这项提议的中心假设是 使用选定的替代物可以无创地评估肿瘤的缺氧和氧合变化 “记号笔”。在所有研究中，我们将使用我们开发的立体定位模板来注册 活体数据和对P02和匹莫硝唑的研究。在目标1中，我们将测试和验证一个新的派生函数 三氟异硝唑(T19F-FMISO)用于低氧显像。我们将确定最优的 剂量作为信号对噪声的要求与低氧成像的特异性之间的平衡，以及 比较18F-咪唑和P02。在目标2中，我们将评估乳酸的定量，动态对比 增强MRI和T19F-FMISO作为氧替代物，并与P02和匹莫硝唑进行对照验证。 在目标2B中，我们将研究抗肿瘤治疗引起的缺氧变化，并使用这些 测量作为潜在的替代物，并与P02、微血管密度和放射生物学检测进行比较。 目标2的目标是确定哪个是缺氧的最佳替代品，并将其应用于目标3。目标3将 使用这些数据来优化缺氧驱动的自杀基因治疗。在《目标3》中，我们将研发一种聚变自杀 基因(胞嘧啶脱氨酶-尿嘧啶磷酸核糖转移酶-CD-UPRT) 低氧反应元件(HRE)，可通过19F核磁共振化学位移成像进行定量成像。 我们将开发这一系统作为一个记者和自杀治疗系统，并评估其有效性和 在平行研究中将其与胸苷激酶进行比较。

Treatment strategies are stratified by risk factors; a goal of stratification into different prognostic groups is to design risk based treatment strategies. Long term survival is determined by "risk factors" that predict prognostic parameters such as probability of local control and risk of developing systemic or metastatic disease. Tumor hypoxia is predictive of both risk of metastases and aggressive local disease. A non-invasive assay to measure hypoxia would provide prognostic information regarding local tumor aggressiveness and metastatic risk for development of risk based therapy, and for monitoring changes in oxygenation with treatment, could impact further therapy. The central hypothesis of this proposal is that tumor hypoxia and changes in oxygenation can be evaluated non-invasively using selected surrogate "markers". In all studies, we will utilize a stereotaxic template we have developed to register both the in vivo data and the p02 and pimonidazole studies. In Aim 1 we will test and validate a novel derivative of misonidazole (trifluoromisonidazole (T19F-FMISO)) for imaging hypoxia. We will determine the optimal dose as a balance between signal to noise requirements vs. specificity for imaging hypoxia, and also compare to 18F-misonidazole and p02. In Aim 2 we will evaluate quantitation of lactate, dynamic contrast enhanced MRI, andT19F-FMISO as oxygen surrogates and validate them against p02 and pimonidazole. In Aim 2B, we will study changes in hypoxia induced by anti-neoplastic therapy and use these measurements as potential surrogate and compare to p02, microvessel density and radiobiological assays. The goal of Aim 2 is to determine which is the best surrogate of hypoxia and apply this in Aim 3. Aim 3 will use this data to optimize hypoxia driven suicide gene therapy. In aim 3, we will develop a fusion suicide gene (Cytosine Deaminase - Uracil Phosphoribosyl Transferase - CD-UPRT), under the control of a hypoxia response element (HRE) which can be quantitatively imaged by 19F NMR chemical shift imaging. We will develop this system as a both a reporter and suicide therapy system and evaluate its efficacy and compare it with thymidine kinase in parallel studies.