Noninvasive Monitoring Glutathione Metabolism in Tumors

描述（由申请人提供）：谷氨酰胺是一种普遍存在的三肽，在正常组织中以高浓度存在，在肿瘤中经常升高。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。细胞氧化还原平衡控制基因表达、分化、增殖和凋亡。在正常组织中，谷胱甘肽保护细胞免受环境压力的影响，癌细胞已经适应了这种防御机制，以保护肿瘤细胞免受治疗的影响。在细胞培养中，我们的实验室已经表明，谷胱甘肽代谢在耐药癌症中持续增加。这些发现得到了许多与谷胱甘肽代谢和患者生存率相关的临床研究的支持。然而，临床研究依赖于肿瘤组织的侵入性重复取样，因为缺乏监测完整肿瘤中谷胱甘肽代谢的方法。在过去的两年中，作为NTH资助的试点项目的一部分，我们成功地开发了一种结合稳定同位素输注的磁共振方法来监测体内谷胱甘肽代谢。该提案建立在试点项目中建立的可行性基础上，并计划使用这些方法非侵入性地监测大鼠R3230乳腺、9 L胶质瘤和FSA纤维肉瘤肿瘤和耐药变体中的谷胱甘肽代谢。将评估与肿瘤生长速率、血管形成和参与氧化还原代谢的关键酶的表达相关的谷胱甘肽代谢。由于细胞内谷胱甘肽水平的下降是细胞凋亡中最早的事件之一，因此通过磁共振检测到的治疗诱导的谷胱甘肽代谢变化将是肿瘤反应的早期指标。由于氧化还原平衡的改变似乎是增殖细胞的普遍特征，特别是癌症，非侵入性监测氧化还原代谢的方法提供了对规划和评估癌症治疗至关重要的过程的新见解。

DESCRIPTION (provided by applicant): Glutathione is a ubiquitous tripeptide found in high concentration in normal tissue and is frequently elevated in tumors. Glutathione and its oxidized disulfide form the primary reduction/oxidation (redox) buffer in the cell. The cellular redox balance controls gene expression, differentiation, proliferation and apoptosis. In normal tissue, glutathione protects the cell from environmental stress and the cancer cell has adapted this defense mechanism to shield tumor cells from the effects of therapy. In cell culture, our laboratory has shown that glutathione metabolism is consistently increased in drug-resistant cancers. These findings are supported by a number of clinical studies relating glutathione metabolism to patient survival. However the clinical studies rely upon invasive repeated sampling of the tumor tissue since methods to monitor glutathione metabolism in intact rumors are lacking. Over the past two years, as part of an NTH-funded pilot project, we succeeded in developing a magnetic resonance method combined with stable isotope infusion to monitor glutathione metabolism in vivo. This proposal builds upon the feasibility established in the pilot project and plans to Use these methods to monitor glutathione metabolism non-invasively in R3230 mammary, 9L glioma and FSA fibrosarcoma tumors and drug-resistant variants in rats. Glutathione metabolism will be assessed in relation to tumor growth rate, vascularization and expression of key enzymes involved in redox metabolism. Since a drop in intracellular glutathione levels is one of the earliest events in apoptosis, therapy-induced changes in glutathione metabolism detected by magnetic resonance will be an early indicator of tumor response. Since altered redox balance appears to be a universal characteristic of proliferating cells in general and cancer in particular, methods to non-invasively monitor redox metabolism offers new insight into a process critical to planning and evaluating cancer therapy.