Glucose Metabolism on Tumor pO2

描述（由申请方提供）：该提案的目的是确定大鼠乳腺肿瘤模型中稳态和高血糖条件下的葡萄糖代谢途径，并操纵这些途径以减少O2消耗并增加肿瘤pO 2。这些都是相关的问题，因为肿瘤缺氧在肿瘤临床行为和治疗反应中起着重要作用。我们采用这种基本上简单的方法，因为葡萄糖和O2代谢彼此紧密相关，并且可以在体内操纵葡萄糖代谢以改善肿瘤pO 2。我们从头颈癌的临床前模型和临床研究中获得了具有启发性的数据，这些数据显示诱导高血糖症后进行O2呼吸可显著改善肿瘤pO 2，其程度远远大于单独治疗。这种方法结合了抑制高血糖症引起的O2消耗（克拉布特里效应）和通过O2呼吸增加的O2输送。其他研究人员也曾单独研究过高氧气体或克拉布特里效应，但没有人将两者结合起来。尽管到目前为止的结果是有希望的，但很明显，我们还没有优化Crabtree效应，这是该项目的目标。 我们的实验室在探索影响葡萄糖代谢的生理机制方面处于独特的地位，通过利用几种新技术，包括：生物发光成像和微透析13 C-NMR，以及一种新型的光纤探针来测量肿瘤中葡萄糖和乳酸摄取动力学。

DESCRIPTION (provided by applicant): The purpose of the proposal is to determine pathways of glucose metabolism under steady state and hyperglycemic conditions in a rat mammary tumor model and manipulate those pathways to reduce O2 consumption and increase tumor pO2. These are pertinent questions because tumor hypoxia plays a major role in tumor clinical behavior and response to therapy. We are taking this fundamentally simple approach because glucose and 02 metabolism are closely tied to one another and glucose metabolism can be manipulated in vivo to improve tumor pO2. We have provocative data from a preclinical model and a clinical study in head and neck cancer that shows induction of hyperglycemia followed by O2 breathing dramatically improves tumor pO2 to an extent far greater than either treatment alone. This approach combines inhibition of O2 consumption by hyperglycemia (Crabtree effect) with increased O2 delivery by O2 breathing. Other investigators have studied hyperoxic gases or the Crabtree effect alone, but none have combined the two. Even though the results thus far are promising, it is clear that we have not optimized the Crabtree effect, which is the goal of this project. Our laboratory is in a unique position to explore physiologic mechanisms that influence glucose metabolism by utilizing several novel techniques including: bioluminescence imaging & microdialysis 13C-NMR, and a novel fiber optic probe to measure glucose and lactate uptake kinetics in tumors.