A. Kuin et al., REDUCTION OF INTRATUMORAL PH BY THE MITOCHONDRIAL INHIBITOR M-IODOBENZYLGUANIDINE AND MODERATE HYPERGLYCEMIA, Cancer research, 54(14), 1994, pp. 3785-3792
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.