The Use of 2-Deoxyglucose in Head and Neck Cancer Therapy

2-脱氧葡萄糖在头颈癌治疗中的应用

• 批准号: 8197317
• 负责人: Douglas Robert Spitz
• 金额: $ 29.83万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197317
• 关键词: Acetic Acids; Biochemical; Biochemistry; Brain; Buthionine Sulfoximine; Cancerous; Carbon Dioxide; Cell Respiration; Cells; Cellular biology; Cisplatin; Clinical; Clinical Trials; Combined Modality Therapy; Deacetylation; Defect; Deoxyglucose; Dose; Drug Metabolic Detoxication; Enzymes; Exposure to; Functional Imaging; Glucose; Glucose Transporter; Glucosephosphate Dehydrogenase; Glutathione; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Human; Hydrogen Peroxide; Image; In Vitro; Ionizing radiation; Lead; Malignant - descriptor; Malignant neoplasm of brain; Mediating; Metabolic; Metabolism; NADP; Natural regeneration; Non-Malignant; Normal Cell; Oxidative Stress; Patients; Pentoses; Peroxidases; Peroxides; Phase; Play; Positron-Emission Tomography; Pre-Clinical Model; Predisposition; Production; Pyruvate; Radiation; Radiation therapy; Radio; Radiosensitization; Reaction; Relative (related person); Reporting; Research; Role; Signal Transduction; Staging; Sulfhydryl Compounds; Techniques; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Tracer; Work; Zidovudine; base; cancer cell; cancer therapy; cell type; chemotherapeutic agent; chemotherapy; combined cancer modality therapy; cytotoxicity; deprivation; glucose analog; glucose metabolism; glucose uptake; hexokinase; improved; in vivo; indexing; inhibitor/antagonist; neoplastic cell; novel; research study; response; thioredoxin peroxidase; tumor; uptake

DESCRIPTION (provided by applicant): Cancer cells in general, relative to normal cells, demonstrate increased glucose metabolism but the mechanism for this is unknown. The clinical utility of these observations has been limited to the use of 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) and Positron Emission Tomography (PET) to identify cancerous tissues. Head and neck cancers show robust signals using FDG-PET imaging that vary between patients, but the significance of the variability is unknown. Glucose metabolism leads to pyruvate and NADPH formation, which function in hydroperoxide detoxification. This has led to the proposal that cancer cells may increase glucose utilization as a compensatory mechanism protecting from intracellular hydroperoxides formed as byproducts of defects in oxidative metabolism. If tumor glucose metabolism is increased in response to excess production of hydroperoxides, inhibition of glucose and hydroperoxide metabolism should lead to oxidative stress and radiosensitization in cancer cells that is proportional to the rate of glucose utilization. The current proposal tests the hypothesis that: the extent to which human head and neck cancer cells increase their uptake and metabolism of glucose is predictive of cancer cell susceptibility to 2DG-induced radio-/chemo-sensitization and hydroperoxide-mediated oxidative stress. Aims 1 and 2 will determine if 2DG-induced radiosensitization can be enhanced by inhibitors of hydroperoxide detoxification [i.e., buthionine sulfoximine or manipulations of glucose-6-phosphate dehydrogenase] and/or chemotherapeutic agents believed to increase oxidative stress [i.e., cisplatin and azidothymidine] in human head and neck cancer cells in vitro and in vivo. Aim 3 will determine if enhancement of 2DG-induced radiosensitization by inhibitors of hydroperoxide detoxification and/or agents that increase oxidative stress is proportional to glucose uptake as determined by FDG-PET imaging in vitro and in vivo. The goal of this work is to provide a novel mechanism based biochemical rationale for the use of glucose metabolic differences and functional imaging to develop biologically guided combined modality therapies to treat head and neck cancer based on tumor specific sensitivity to metabolic oxidative stress. PUBLIC HEALTH RELEVANCE: Increased sensitivity to glucose deprivation-induced oxidative stress in tumor vs. normal cells, has led to the hypothesis that inhibitors of glucose and hydroperoxide metabolism [i.e., 2-deoxyglucose (2DG) and buthionine sulfoximine] could be combined with therapeutic agents that increase oxidative stress (radiation, Cisplatin, and azidothymidine) to improve responses during cancer therapy. Furthermore since FDG-PET imaging can be used as a non-invasive marker of glucose metabolism, tumors with greater FDG uptake should respond better to 2-deoxyglucose-based combined modality therapies via enhancement of oxidative stress. If these hypotheses could be confirmed by the experiments in this proposal, they could provide the first mechanism based biochemical rationale for the use of glucose metabolic differences to develop biologically guided combined modality therapies to treat head and neck cancer.

描述（由申请人提供）：相对于正常细胞，癌细胞通常表现出葡萄糖代谢增加，但其机制尚不清楚。这些观察结果的临床应用仅限于使用2-[F-18]-氟-2-脱氧-D-葡萄糖（FDG）和正电子发射断层扫描（PET）来识别癌组织。使用FDG-PET成像，头颈部癌症显示出强大的信号，这些信号在患者之间存在差异，但变异性的意义尚不清楚。葡萄糖代谢导致丙酮酸和NADPH形成，其在氢过氧化物解毒中起作用。这导致提出癌细胞可以增加葡萄糖利用作为保护免受作为氧化代谢缺陷的副产物形成的细胞内氢过氧化物的补偿机制。如果肿瘤葡萄糖代谢响应于氢过氧化物的过量产生而增加，则葡萄糖和氢过氧化物代谢的抑制应导致癌细胞中与葡萄糖利用率成比例的氧化应激和放射增敏。目前的提议测试了以下假设：人类头颈癌细胞增加其葡萄糖摄取和代谢的程度可预测癌细胞对2DG诱导的放射/化学敏化和过氧化氢介导的氧化应激的易感性。目的1和2将确定2DG诱导的放射增敏是否可以通过氢过氧化物解毒的抑制剂增强[即，丁硫氨磺酰亚胺或葡萄糖-6-磷酸脱氢酶的操作]和/或被认为增加氧化应激的化疗剂[即，顺铂和叠氮胸苷]在人头颈癌细胞中的体外和体内研究。目的3将确定通过氢过氧化物解毒抑制剂和/或增加氧化应激的药剂增强2DG诱导的放射增敏是否与葡萄糖摄取成比例，如通过体外和体内FDG-PET成像所确定的。这项工作的目标是提供一种新的机制为基础的生化原理，使用葡萄糖代谢差异和功能成像开发生物指导的综合模式治疗，以治疗头颈癌的肿瘤特异性敏感性代谢氧化应激。 公共卫生相关性：与正常细胞相比，肿瘤细胞对葡萄糖剥夺诱导的氧化应激的敏感性增加，这导致了葡萄糖和氢过氧化物代谢的抑制剂[即，2-在癌症治疗期间，可以将[脱氧葡萄糖（2DG）和丁硫氨磺酰亚胺]与增加氧化应激的治疗剂（放射、顺铂和叠氮胸苷）组合以改善反应。此外，由于FDG-PET成像可用作葡萄糖代谢的非侵入性标记物，因此具有更大FDG摄取的肿瘤应通过增强氧化应激对基于2-脱氧葡萄糖的联合模式治疗有更好的反应。如果这些假设可以通过本提案中的实验得到证实，则它们可以为使用葡萄糖代谢差异来开发生物指导的联合模式疗法以治疗头颈部癌症提供第一个基于机制的生化原理。