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: 7613858
• 负责人: Douglas Robert Spitz
• 金额: $ 30.79万
• 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/7613858
• 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; Energy Metabolism; 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; Pyruvates; 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; inorganic phosphate; 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. 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）：通常，相对于正常细胞，癌细胞表明葡萄糖代谢增加，但其机制尚不清楚。这些观察结果的临床实用性仅限于使用2- [F-18] -Fluoro-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成像在患者之间变化，头颈部癌症显示出强大的信号，但可变性的重要性尚不清楚。葡萄糖代谢导致丙酮酸和NADPH形成，在氢过氧解毒中起作用。这导致了这样的建议，即癌细胞可能会增加葡萄糖利用，作为一种补偿机制，可保护氧化代谢中缺陷的副产物形成的细胞内氢过氧化物。如果肿瘤葡萄糖代谢响应过量的氢过氧化物的产生，则抑制葡萄糖和氢过氧化代谢应导致癌细胞中与葡萄糖利用率成比例的癌细胞的氧化应激和放射性化。当前的提案检验了以下假设：人头和颈部癌细胞在多大程度上增加了葡萄糖的摄取和代谢，可以预测癌细胞对2DG诱导的无线电/化学敏感性以及氢过氧化物介导的氧化应激的敏感性。目的1和2将确定2DG诱导的放射敏化是否可以通过氢过氧解毒的抑制剂来增强[即，丁烷硫氨酸磺氧胺或6-磷酸葡萄糖脱氢酶]和/或被认为会增加氧化胁迫的化学症状和核心疗法的化学疗法[I.ESPLOSID]的化学疗法[I.ESPLOSID]，COLISPLOSIN的疗法和A ZISPLATORINGINS和AZISPLATRONING蛋白[I.ESISPLATROSID]和体内。 AIM 3将确定通过氢过氧解毒抑制剂和/或增加氧化应激的药物的抑制剂增强2DG诱导的放射敏化，这与FDG-PET在体外和体内通过FDG-PET成像确定的葡萄糖摄取成正比。这项工作的目的是提供一种新型的基于机制的生化原理，用于使用葡萄糖代谢差异和功能成像，以开发出生物学指导的联合模态疗法，以基于对代谢氧化应激的肿瘤特异性敏感性来治疗头颈癌。 公共卫生相关性：对葡萄糖剥夺引起的肿瘤与正常细胞中氧化应激的敏感性提高，导致假设是，葡萄糖和氢过氧代谢的抑制剂[即2-脱氧葡萄糖（2DG）和丁氨氨基硫氨酸的压力可能会增加氧化剂的氧化剂和氧化剂，从而增加氧化剂的氧化剂，并增加氧化剂的氧化剂，并增加叠氮噻嗪）以改善癌症治疗过程中的反应。此外，由于FDG-PET成像可以用作葡萄糖代谢的非侵入性标记，因此，FDG摄取较高的肿瘤应通过增强氧化应激，对基于2-脱氧葡萄糖的组合式疗法应更好地反应。如果这些假设可以通过该提案中的实验确认，则可以为使用葡萄糖代谢差异提供第一个基于机制的生化原理，以开发生物学指导的合并方式疗法来治疗头颈癌。