Magnetic Resonance Imaging of Glutathione in Tumors

说明(申请人提供)：谷胱甘肽是一种三肽，通常在正常组织中浓度较高，在肿瘤组织中经常升高。谷胱甘肽及其氧化的二硫化物在细胞内形成主要的还原/氧化(Redox)缓冲液。细胞中的氧化还原平衡控制着基因表达、细胞分化、增殖和凋亡，因此，这种平衡在癌症中可能会升高也就不足为奇了。在正常组织中，谷胱甘肽保护细胞免受毒物的伤害，而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。这会导致耐药肿瘤中谷胱甘肽代谢的进一步升高。因此，从正常组织和肿瘤组织中提取的谷胱甘肽的准确测定对于预测患者的治疗反应是非常有价值的。这项建议概述了磁共振成像(MRI)方法的发展，以非侵入性地监测正常组织和肿瘤组织中的谷胱甘肽代谢。将对几种MRI方法进行评估，包括使用1H编辑、2H核磁共振和13C化学位移成像。使用最灵敏的方法，从植入大鼠侧翼的9L胶质瘤肿瘤中获得的体内谷胱甘肽含量图像将与组织提取液中生化测量的浓度进行比较。所有的成像方式都将测量静态谷胱甘肽，并需要使用稳定的同位素掺入。基于同位素掺入的方法还可以监测组织中谷胱甘肽的代谢率。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、分化和凋亡中的独特作用，对谷胱甘肽代谢的非侵入性监测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.