Glucose Metabolism on Tumor pO2

描述(申请人提供)：该提案的目的是确定在稳定状态和高血糖条件下的大鼠乳腺肿瘤模型中的葡萄糖代谢途径，并操纵这些途径来降低O2消耗和增加肿瘤的PO2。这些都是相关的问题，因为肿瘤缺氧在肿瘤的临床行为和治疗反应中起着重要作用。我们之所以采取这种从根本上来说很简单的方法，是因为葡萄糖和02的代谢是紧密联系在一起的，并且可以在体内操纵葡萄糖代谢来改善肿瘤的pO2。我们有来自临床前模型和头颈癌临床研究的具有挑衅性的数据，这些数据表明，诱导高血糖后呼吸氧气显着改善肿瘤的pO2，其程度远远超过任何一种单独治疗。这种方法结合了高血糖对氧气消耗的抑制(克拉布特里效应)和氧气呼吸增加氧气输送。其他研究人员已经单独研究了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很有希望，但很明显，我们并没有优化克拉布特里效应，这是本项目的目标。我们的实验室利用几项新技术来探索影响葡萄糖代谢的生理机制，包括：生物发光成像和微透析13C-核磁共振，以及一种新的光纤探针来测量肿瘤中葡萄糖和乳酸的摄取动力学。

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.