Noninvasive Monitoring Glutathione Metabolism in Tumors

谷胱甘肽是一种普遍存在的三肽，在正常组织中浓度很高，在 肿瘤。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。 细胞氧化还原平衡控制基因的表达、分化、增殖和凋亡。正常情况下 组织，谷胱甘肽保护细胞免受环境压力，癌细胞已经适应了这种防御 保护肿瘤细胞免受治疗影响的机制。在细胞培养方面，我们的实验室已经证明 在耐药癌症中，谷胱甘肽代谢持续增加。这些发现得到了一个 将谷胱甘肽代谢与患者生存联系起来的临床研究的数量。然而，临床研究依赖于 对肿瘤组织进行侵入性重复采样，因为方法是监测完整的谷胱甘肽代谢 目前尚无传言。在过去的两年里，作为第n个资助的试点项目的一部分，我们成功地 磁共振结合稳定同位素输注监测谷胱甘肽的研究 体内代谢。该提案建立在试点项目确定的可行性的基础上，并计划使用 这些方法无创监测R3230乳腺、9L胶质瘤和FSA的谷胱甘肽代谢 大鼠纤维肉瘤肿瘤和耐药变异体。谷胱甘肽代谢的评估将与以下方面有关 肿瘤生长速度、血管生成和氧化还原代谢关键酶的表达。因为一个 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，治疗诱导的 磁共振检测到的谷胱甘肽代谢将是肿瘤反应的早期指标。自.以来 氧化还原平衡改变似乎是一般增殖细胞和癌症的普遍特征。 特别是，非侵入性监测氧化还原代谢的方法提供了对以下过程至关重要的新见解 规划和评估癌症治疗。

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.