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: 8386631
• 负责人: Douglas Robert Spitz
• 金额: $ 28.03万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386631
• 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; 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; public health relevance; 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.

描述（由申请人提供）：相对于正常细胞，癌细胞一般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用途仅限于使用 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。头颈癌使用 FDG-PET 成像显示出强大的信号，这些信号因患者而异，但差异的意义尚不清楚。葡萄糖代谢导致丙酮酸和 NADPH 形成，其在氢过氧化物解毒中发挥作用。这导致有人提出，癌细胞可能会增加葡萄糖的利用，作为一种补偿机制，防止细胞内因氧化代谢缺陷的副产物而形成氢过氧化物。如果肿瘤葡萄糖代谢因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的氧化应激和放射增敏，其与葡萄糖利用率成正比。目前的提案测试了以下假设：人类头颈癌细胞增加葡萄糖摄取和代谢的程度可以预测癌细胞对 2DG 诱导的放射/化学敏化和氢过氧化物介导的氧化应激的敏感性。目标 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抑制剂 [即丁硫氨酸亚砜亚胺或葡萄糖 6-磷酸脱氢酶的操作] 和/或据信增加氧化应激的化疗药物 [即顺铂和叠氮胸苷] 来增强] 在体外和体内的人类头颈癌细胞中。目标 3 将确定氢过氧化物解毒抑制剂和/或增加氧化应激的药物对 2DG 诱导的放射增敏作用的增强是否与体外和体内 FDG-PET 成像确定的葡萄糖摄取成正比。这项工作的目标是提供一种基于生化原理的新机制，利用葡萄糖代谢差异和功能成像来开发生物引导的组合疗法，根据肿瘤对代谢氧化应激的特异性敏感性来治疗头颈癌。

项目成果

Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials.

局部晚期肺癌和胰腺癌接受放疗和化疗的同时采用生酮饮食：爱荷华大学两项 1 期临床试验的经验。

• 发表时间: 2017-06
• 影响因子: 3.4
• 作者: Zahra, Amir;Fath, Melissa A;Opat, Emyleigh;Mapuskar, Kranti A;Bhatia, Sudershan K;Ma, Daniel C;Rodman III, Samuel N;Snyders, Travis P;Chenard, Catherine A;Eichenberger;Bodeker, Kellie L;Ahmann, Logan;Smith, Brian J;Vollstedt
• 通讯作者: Vollstedt

Exploring the electrostatic repulsion model in the role of Sirt3 in directing MnSOD acetylation status and enzymatic activity.

探索 Sirt3 在指导 MnSOD 乙酰化状态和酶活性中的作用的静电排斥模型。

• DOI: 10.1016/j.freeradbiomed.2012.06.020
• 发表时间: 2012-08-15
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Zhu, Yueming;Park, Seong-Hoon;Ozden, Ozkan;Kim, Hyun-Seok;Jiang, Haiyan;Vassilopoulos, Athanassios;Spitz, Douglas R.;Gius, David
• 通讯作者: Gius, David