Nuclear Magnetic Resonance Imaging of Tumor Hypoxia

治疗策略按风险因素分层;分层到不同预后组的目标是 设计基于风险的治疗策略。长期生存是由“风险因素”决定的， 预后参数，如局部控制的可能性和发生系统性或转移性疾病的风险 疾病肿瘤缺氧可预测转移和侵袭性局部疾病的风险。一 测量缺氧的非侵入性测定将提供关于局部肿瘤的预后信息 侵袭性和转移风险，用于开发基于风险的治疗，并用于监测 氧合治疗可能影响进一步治疗。这一提议的核心假设是， 肿瘤缺氧和氧合变化可以使用选择的替代物非侵入性地评估 “标记”。在所有的研究中，我们将利用我们开发的立体定位模板来记录两个在 体内数据和P02和哌莫硝唑研究。在目标1中，我们将测试和验证一种新的衍生物， 米索硝唑（三氟米索硝唑（T19 F-FMISO））用于缺氧成像。我们将确定最佳的 剂量作为信噪比要求与成像缺氧特异性之间的平衡，以及 与18F-米索硝唑和p02相比。在目标2中，我们将评估乳酸定量、动态对比度 增强MRI和T19 F-FMISO作为氧替代物，并验证它们对p02和pimonidazole的作用。 在目标2B中，我们将研究抗肿瘤治疗诱导的缺氧变化，并使用这些变化。 测量值作为潜在的替代物，并与P02、微血管密度和放射生物学测定进行比较。 目标2的目标是确定哪一个是缺氧的最佳替代物，并将其应用于目标3。目标3将 使用该数据来优化缺氧驱动的自杀基因疗法。在目标3中，我们将开发一种聚变自杀 基因（胞嘧啶脱氨酶-尿嘧啶磷酸核糖转移酶- CD-UPRT），在一个 缺氧反应元件（HRE），其可以通过19 F NMR化学位移成像定量成像。 我们将开发这个系统作为一个报告和自杀治疗系统，并评估其疗效， 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.