Reduction of intratumoral pH by the mitochondrial inhibitor m-iodobenzylguanidine and moderate hyperglycemia

Abstract

The interstitial pH of RIF-1 tumors was selectively lowered by i.p. administration of the mitochondrial inhibitor meta-iodobenzylguanidine (MIBG; 40-100 mg/kg), supported by sustained moderate hyperglycemia (plasma glucose concentration, 14 mM) in rats or by a single i.p. bolus injection of glucose (1.5 g/kg) in mice. Responses were evaluated in a multicenter study by pH measurements with semimicroelectrodes and 31P magnetic resonance spectroscopy, by biochemical analysis of tissue and plasma levels of glucose and lactate, and by positron emission tomography analysis of 2-[18F]fluoro-2-deoxy-D-glucose uptake. In both schedules, treatment with MIBG and glucose reduced the mean intratumoral pH as recorded with semimicroelectrodes to 6.2. In the mouse model, treatment with MIBG plus glucose was accompanied by a 2-3-fold stimulation of 2-[18F]fluoro-2-deoxy-D-glucose uptake and a corresponding increase in tumor glucose content. Responses were maximal in male mice with tumors of 0.2-0.8 g. 31P magnetic resonance spectroscopy analysis revealed no changes in intracellular pH or metabolic status, indicating that only extracellular pH was affected. MIBG was synergistic with bolus or continuous glucose administrations by a dual mechanism. The drug reduced by up to 5-fold the amount of glucose required for effective reduction of intratumoral pH and promoted the availability of (extra) glucose to tumor tissue in a stress-related, sympathomimetic response. Moreover, by converting oxic tumor cells into functionally hypoxic cells, combined treatment resulted in a more homogeneous decrease in intratumoral pH which included better perfused peripheral tumor areas. The effects of combined treatment on tumor glucose metabolism could be monitored noninvasively by 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography analysis.