PET IMAGING OF HYPOXIA WITH EF1 AND EF5

最近的数据提供了令人信服的证据，证明缺氧肿瘤（子宫颈、头颈部、软组织肉瘤）对最广泛使用的治疗形式具有耐药性。此外，缺氧肿瘤容易发生转移。因此，肿瘤缺氧的早期发现可能在选择最合适的治疗方法中发挥重要作用。组织缺氧的非侵入性检测将适用于所有肿瘤，其中许多肿瘤无法通过侵入性方法获得，以帮助在个体患者基础上选择最合适的治疗方法。这项工作包括在啮齿动物肿瘤模型中详细测试两种2-硝基咪唑EF1和EF5。这些化合物被代谢还原，形成共价细胞内加合物，其速率在严重缺氧时最大，并随着氧浓度的增加而降低，具有一级抑制动力学。然后，结合的加合物可以用各种方法检测，作为测量组织缺氧的替代品。EF5的结合已经用免疫组织化学技术进行了彻底的表征，并被证明可以预测啮齿动物个体肿瘤对辐射的反应。EF5已被FDA批准用于人类，目前正处于使用此类方法的I期临床试验中。该试验的结果显示，EF5没有相关的毒性，并且关于EF5检测预后相关缺氧能力的轶事信息令人鼓舞。EF5及其亲水性更强的类似物EF1最近被标记为18F，从而可以通过正电子发射断层扫描（PET）检测药物和加合物。因此，我们将能够比较使用免疫组织化学在非常高分辨率下对缺氧的侵入性测量与低分辨率下的非侵入性测量（PET）。我们计划的研究将允许详细测试无创缺氧成像的几个关键方面：这些包括药物浓度的影响，药物极性和成像算法和分辨率的优化。最后一种方法将大大受益于宾夕法尼亚大学目前正在开发的一种新型高分辨率PET相机。我们的总体假设是，使用适当的PET显像剂评估缺氧将预测个体肿瘤的辐射反应。还应该指出的是，缺氧的检测在其他病理条件下也有广泛的应用，包括中风、心脏病发作和伤口愈合。

Recent data has provided compelling evidence that hypoxic tumors (cervix, head and neck, soft tissue sarcoma) are resistant to the most widely used forms of therapy. In addition, hypoxic tumors are prone to metastasis. Thus, the early detection of tumor hypoxia is likely to play an important role in choosing the most appropriate therapies. A non-invasive assay for tissue hypoxia would be applicable to all tumors, many of which cannot be accessed by invasive methods, to aid in the selection the most appropriate therapy on an individual patient basis. The proposed work involves the detailed testing of two 2-nitroimidazoles, EF1 and EF5, in rodent tumor models. Such compounds are metabolically reduced forming covalent intracellular adducts at a rate which is maximal in severe hypoxia and decreases, with first order inhibition kinetics, as the oxygen concentration increases. The bound adducts can then be detected in various ways as a surrogate for the measurement of tissue hypoxia. Binding of EF5 has been thoroughly characterized using immunohistochemical techniques and has been shown to predict individual tumor response to radiation in rodents. EF5 is FDA approved for use in humans and is currently in phase I clinical trials using such methods. Results from this trial have shown no EF5-related toxicity, and anectdotal information regarding the ability of EF5 to detect prognosis-related hypoxia are encouraging. EF5, and its much more hydrophilic analog, EF1, have recently been labelled with 18F, allowing drug and adduct detection by positron emission tomography (PET). Thus, we will be able to compare invasive measurement of hypoxia, at very high resolution using immunohistochemistry, with non-invasive measurements (PET) at lower resolution. Our planned studies will allow several key aspects of non-invasive hypoxia imaging to be tested in detail: these include the effects of drug concentration, drug polarity and optimization of imaging algorithms and resolution. The last of these will greatly benefit from a new high-resolution PET camera under current development at the University of Pennsylvania. Our overall hypothesis is that assessment of hypoxia using appropriate PET imaging agents will predict radiation response in individual tumors. It should also be noted that the detection of hypoxia has wide-ranging applications in other pathologic conditions including stroke, heart attack, and wound healing.