Magnetic Resonance Imaging of Glutathione in Tumors

描述（由申请人提供）：谷氨酰胺是一种三肽，通常在正常组织中以高浓度存在，在肿瘤组织中经常升高。谷氨酸及其氧化的二硫化物形成细胞中的主要还原/氧化（氧化还原）缓冲液。细胞中的氧化还原平衡控制基因表达、细胞分化、增殖和凋亡，因此，这种平衡在癌症中可能升高并不奇怪。在正常组织中，谷胱甘肽保护细胞免受有毒物质的侵害，癌细胞已经适应了这种防御机制，以保护细胞免受抗癌治疗的影响。这导致治疗抗性肿瘤中谷胱甘肽代谢的进一步升高。因此，从正常和肿瘤组织提取物中谷胱甘肽的准确测定已被证明是非常宝贵的预测患者的治疗反应。该提案概述了磁共振成像（MRI）方法的发展，以非侵入性监测谷胱甘肽在正常和肿瘤组织中的代谢。将评价几种MRI方法，包括使用1H编辑、2 H NMR和13 C化学位移成像。使用最灵敏的方法，将从植入大鼠侧腹的9 L神经胶质瘤肿瘤中获得的谷胱甘肽含量的体内图像与组织提取物中生物化学测量的浓度进行比较。所有的成像方式将测量静态谷胱甘肽，并需要使用稳定的同位素掺入。基于同位素稀释的方法还允许监测组织中谷胱甘肽代谢的速率。这些类型的动态研究可能与测量静态谷胱甘肽水平对肿瘤分期和预测治疗反应一样重要。由于谷胱甘肽在细胞增殖、分化和凋亡中发挥着独特的作用，无创监测谷胱甘肽代谢将为肿瘤组织的诊断和预后提供新的信息。

DESCRIPTION (provided by applicant):Glutathione is a tripeptide normally found in high concentration in normal tissue and frequently elevated in tumor tissue. Glutathione and its oxidized disulfide form the primary reduction/oxidation (redox) buffer in cells. The redox balance in the cell controls gene expression, cell differentiation, proliferation and apoptosis and, therefore, it is not surprising that this balance may be elevated in cancer. In normal tissue glutathione protects the cell from toxicants and the cancer cell has adapted this defense mechanism to shield cells from the effects of anticancer therapies. This results in further elevations in glutathione metabolism in therapy-resistant tumors. Therefore, the accurate determination of glutathione in extracts from normal and tumor tissue has proven to be invaluable to predicting therapy response in patients. This proposal outlines the development of magnetic resonance imaging (MRI) methods to non-invasively monitor glutathione metabolism in normal and tumor tissue. Several MRI methods will be evaluated including the use of 1H-editing, 2H NMR and 13C-chemical shift imaging. Using the most sensitive method, in vivo images of glutathione content obtained from 9L glioma tumors implanted in the flank of rats will be compared to the concentrations measured biochemically in tissue extracts. All of the imaging modalities will measure static glutathione and require the use of stable isotope incorporation. Isotope incorporation-based methods also allow monitoring of the rate of glutathione metabolism in tissue. These types of dynamic studies may be as important as measuring static glutathione levels to stage tumors and predict therapy response. Due to the unique role played by glutathione in cell proliferation, differentiation and apoptosis, the non-invasive monitoring of glutathione metabolism would offer novel diagnostic and prognostic information on the tumor tissue.