Noninvasive Monitoring Glutathione Metabolism in Tumors

无创监测肿瘤中的谷胱甘肽代谢

• 批准号: 7342396
• 负责人: MICHAEL GAMCSIK
• 金额: $ 26.01万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-17 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342396
• 关键词: Address; Aftercare; Amino Acids; Antioxidants; Apoptosis; Arts; Biochemistry; Biological Models; Biomedical Engineering; Biopsy Specimen; Blood Vessels; Buffers; Cells; Characteristics; Clinical Research; Cultured Cells; Defense Mechanisms; Development; Disulfides; Drops; Drug resistance; Duke Comprehensive Cancer Center; Enzymes; Equilibrium; Event; Florida; Funding; Gene Expression; Glioma; Glutathione; Glutathione Metabolism Pathway; Growth; Heterogeneity; Infusion procedures; Invasive; Investigation; Isotope Labeling; Label; Laboratories; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary gland; Measures; Metabolic; Metabolism; Methods; Modeling; Monitor; Normal tissue morphology; North Carolina; Numbers; Oxidation-Reduction; Patients; Pilot Projects; Play; Process; Proliferating; Rate; Rattus; Reproducibility; Research Personnel; Role; Sampling; Sampling Errors; Stress; System; Testing; Therapeutic; Tissues; Tumor Tissue; Universities; Variant; Vascularization; cancer cell; cancer therapy; chemotherapy; design; fibrosarcoma; in vivo; insight; monolayer; neoplastic cell; programs; research study; response; size; stable isotope; success; therapy resistant; tumor; tumor growth; uptake

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.

谷胱甘肽是一种普遍存在的三肽，在正常组织中浓度很高，并且在正常组织中经常升高。 肿瘤。谷胱甘肽及其氧化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。正常情况下 在组织中，谷胱甘肽保护细胞免受环境压力，而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。在细胞培养中，我们的实验室表明 在耐药癌症中，谷胱甘肽代谢持续增加。这些发现得到了以下证据的支持 许多有关谷胱甘肽代谢与患者生存的临床研究。然而临床研究依赖 自从监测完整的谷胱甘肽代谢的方法以来，对肿瘤组织进行侵入性重复取样 缺乏谣言。在过去的两年里，作为 NTH 资助的试点项目的一部分，我们成功地 开发磁共振方法结合稳定同位素输注来监测谷胱甘肽 体内代谢。该提案建立在试点项目中建立的可行性之上，并计划使用 这些方法可无创监测 R3230 乳腺、9L 神经胶质瘤和 FSA 中的谷胱甘肽代谢 大鼠纤维肉瘤肿瘤和耐药变异。谷胱甘肽代谢将根据以下方面进行评估 肿瘤生长速率、血管化和参与氧化还原代谢的关键酶的表达。自从一个 细胞内谷胱甘肽水平下降是细胞凋亡中最早的事件之一，治疗引起的细胞凋亡变化 磁共振检测到的谷胱甘肽代谢将成为肿瘤反应的早期指标。自从 氧化还原平衡的改变似乎是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为对氧化还原代谢至关重要的过程提供了新的见解。 规划和评估癌症治疗。