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

描述(申请人提供)：一般说来，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)来识别癌症组织。使用FDG-PET成像，头颈部癌症显示出强烈的信号，但不同患者之间的信号不同，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，这两种物质在过氧化氢解毒中起作用。这导致了一种建议，即癌细胞可能会增加葡萄糖的利用，作为一种补偿机制，保护细胞内的过氧化氢，作为氧化代谢缺陷的副产品形成。如果肿瘤葡萄糖代谢因过量产生过氧化氢而增加，抑制葡萄糖和过氧化氢代谢应该会导致癌细胞的氧化应激和放射增敏，这与葡萄糖利用率成正比。目前的提议验证了这样的假设：人头颈部癌细胞对葡萄糖的摄取和代谢增加的程度预示着癌细胞对2DG诱导的放/化疗敏化和过氧化氢介导的氧化应激的敏感性。AIMS 1和2将确定在体外和体内，过氧化氢解毒抑制剂[即丁硫氨酸亚磺胺或葡萄糖-6-磷酸脱氢酶]和/或被认为增加氧化应激[即顺铂和叠氮胸苷]的化疗药物是否可以增强2DG诱导的放射增敏。目的3将通过体外和体内FDG-PET成像确定过氧化氢解毒抑制剂和/或增加氧化应激的药物对2DG诱导的放射增敏的增强作用是否与葡萄糖摄取成正比。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引导的综合疗法来治疗头颈癌提供一种新的机制基础。 公共卫生相关性：与正常细胞相比，肿瘤细胞对缺糖诱导的氧化应激反应更加敏感，这导致了一种假说，即葡萄糖和过氧化氢代谢的抑制剂[即2-脱氧葡萄糖(2DG)和丁硫氨酸亚磺胺]可与增加氧化应激反应的治疗药剂(放射、顺铂和叠氮胸苷)联合使用，以改善癌症治疗期间的反应。此外，由于FDG-PET成像可以作为糖代谢的非侵入性标记，FDG摄取率较高的肿瘤应该通过增强氧化应激而对基于2-脱氧葡萄糖的联合治疗有更好的反应。如果这些假说能够被这项提议中的实验所证实，它们可以为利用葡萄糖代谢差异来开发生物引导的综合疗法来治疗头颈癌提供第一个基于机制的生化原理。

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.