REDUCTION OF INTRATUMORAL PH BY THE MITOCHONDRIAL INHIBITOR M-IODOBENZYLGUANIDINE AND MODERATE HYPERGLYCEMIA

The interstitial pH of RIF-1 tumors was selectively lowered by i.p. ad ministration of the mitochondrial inhibitor meta-iodobenzylguanidine ( MIBG; 40-100 mg/kg), supported by sustained moderate hyperglycemia (pl asma glucose concentration, 14 mM) in rats or by a single i.p. bolus i njection of glucose (1.5 g/kg) in mice. Responses were evaluated is a multicenter study by pH measurements with semimicroelectrodes and P-31 magnetic resonance spectroscopy, by biochemical analysis of tissue an d plasma levels of glucose and lactate, and by positron emission tomog raphy analysis of 2-[F-18]fluoro-2-deoxy-D-glucose uptake. In both sch edules, treatment with MIBG and glucose reduced the mean intratumoral pH as recorded with semimicroelectrodes to 6.2. In the mouse model, tr eatment with MIBG plus glucose was accompanied by a 2-3-fold stimulati on of 2-[F-18]fluoro-2-deoxy-D-glucose uptake and a corresponding incr ease in tumor glucose content. Responses were maximal in male mice wit h tumors of 0.2-0.8 g. P-31 magnetic resonance spectroscopy analysis r evealed no changes in intracellular pH or metabolic status, indicating that only extracellular pH was affected. MIBG was synergistic with bo lus or continuous glucose administrations by a dual mechanism. The dru g 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 c ells, combined treatment resulted in a more homogeneous decrease in in tratumoral pH which included better perfused peripheral tumor areas. T he effects of combined treatment on tumor glucose metabolism could be monitored noninvasively by 2-[F-18]fluoro 2-deoxy-D-glucose positron e mission tomography analysis.