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.
