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

描述（由申请人提供）：一般而言，相对于正常细胞，癌细胞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，头颈部癌症显示出不同患者之间存在差异的强大信号，但这种差异的意义尚不清楚。葡萄糖代谢导致丙酮酸和NADPH的形成，它们在过氧化氢解毒中起作用。这导致人们提出，癌细胞可能增加葡萄糖的利用，作为一种代偿机制，保护细胞内氢过氧化物免受氧化代谢缺陷的副产物的侵害。如果肿瘤葡萄糖代谢因过度产生氢过氧化物而增加，抑制葡萄糖和氢过氧化物代谢应导致癌细胞氧化应激和放射致敏，这与葡萄糖利用率成正比。目前的提议验证了这样一个假设：人类头颈部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/化学致敏和氢过氧化物介导的氧化应激的易感性。目的1和2将确定氢过氧化物解毒抑制剂（如丁硫氨酸亚砜胺或葡萄糖-6-磷酸脱氢酶的操作）和/或被认为会增加氧化应激的化疗药物（如顺铂和氮杂胸嘧啶）是否可以在体外和体内增强2dg诱导的放射增敏。目的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。这项工作的目的是为利用葡萄糖代谢差异和功能成像来开发基于肿瘤对代谢氧化应激的特异性敏感性的生物学指导联合治疗头颈癌提供一种基于生化原理的新机制。

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.