title: Serial in vivo spectroscopic nuclear magnetic resonance imaging of lactate and extracellular pH in rat gliomas shows redistribution of protons away from sites of glycolysis.
abstract: The acidity of the tumor microenvironment aids tumor growth, and mechanisms causing it are targets for potential therapies. We have imaged extracellular pH (pHe) in C6 cell gliomas in rat brain using 1H magnetic resonance spectroscopy in vivo. We used a new probe molecule, ISUCA [(+/-)2-(imidazol-1-yl)succinic acid], and fast imaging techniques, with spiral acquisition in k-space. We obtained a map of metabolites [136 ms echo time (TE)] and then infused ISUCA in a femoral vein (25 mmol/kg body weight over 110 min) and obtained two consecutive images of pHe within the tumor (40 ms TE, each acquisition taking 25 min). pHe (where ISUCA was present) ranged from 6.5 to 7.5 in voxels of 0.75 microL and did not change detectably when [ISUCA] increased. Infusion of glucose (0.2 mmol/kg.min) decreased tumor pHe by, on average, 0.150 (SE, 0.007; P < 0.0001, 524 voxels in four rats) and increased the mean area of measurable lactate peaks by 54.4 +/- 3.4% (P < 0.0001, 287 voxels). However, voxel-by-voxel analysis showed that, both before and during glucose infusion, the distributions of lactate and extracellular acidity were very different. In tumor voxels where both could be measured, the glucose-induced increase in lactate showed no spatial correlation with the decrease in pHe. We suggest that, although glycolysis is the main source of protons, distributed sites of proton influx and efflux cause pHe to be acidic at sites remote from lactate production.
authors: Institut National de la Santé et de la Recherche Médicale, U836, France.
authors: Peggy
authors: P
authors: Provent
authors: Marina
authors: M
authors: Benito
authors: Bassem
authors: B
authors: Hiba
authors: Régine
authors: R
authors: Farion
authors: Pilar
authors: P
authors: López-Larrubia
authors: Paloma
authors: P
authors: Ballesteros
authors: Chantal
authors: C
authors: Rémy
authors: Christoph
authors: C
authors: Segebarth
authors: Sebastián
authors: S
authors: Cerdán
authors: Jonathan A
authors: JA
authors: Coles
authors: María Luisa
authors: ML
authors: García-Martín
mesh_terms: D000818:Animals; D005910:Glioma / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D013386:Succinates / Q000494:pharmacology
chemical_list: D011522:Protons; D013386:Succinates; D019344:Lactic Acid; D005947:Glucose