Modulations of intra and extracellular pH in tumor variants defective in either respiration or glycolysis, observed by in vivo MRS

Introduction HIF-induced tumor neovascularization has become an important target of anticancer therapy. While the current use of angiogenesis inhibitors aims at converting cancer to a chronic manageable disease [1], further modifications of the hypoxic tumor microenvironment are needed to achieve complete tumor regression. It has previously been proposed to take advantage of the increased production of protons under drug-enhanced hypoxia [2]. Thus, the central idea is to treat tumors with additional drugs designed to decrease intracellular and increase extracellular pH. The purpose of the current study is to contribute to the validation of the suggested treatment method. Effects of modulations of multiple mechanisms of glycolytic activity and pH regulation on intracellular and extracellular pH (pHi, pHe) are being investigated. To this end, we chose a model system (ras-transformed fibroblasts) in which several mutations where engineered to manipulate glycolysis and pH. Effects of these mutations were studied in xenograft models of nude mice, using in vivo magnetic resonance spectroscopy and imaging. Intra and extracellular pH were determined simultaneously, in conjunction with tumor morphology and necrosis, and were complemented with histological data.