Estimations of intra- and extracellular volume and pH by 31P magnetic resonance spectroscopy: effect of therapy on RIF-1 tumours.
Quantification of metabolite or drug concentrations in living tissues requires determination of intra- and extracellular volumes. This study demonstrates how this can be achieved non-invasively by 31P magnetic resonance spectroscopy (MRS) employing dimethyl methylphosphonate (DMMP) as a marker of total water space, 3-aminopropylphosphonate (3-APP) as a marker of extracellular space and P and 3-APP as markers of intracellular pH (pH) and extracellular pH (pHe) respectively. The MRS measurements of the tumour volumes were validated by classic radiolabelling methods using 3H2O and [14C]inulin as markers of total and extracellular space respectively. The extracellular volume fraction measured by radiolabelling of RIF-1 tumours was 23 +/- 0.83% (mean +/- s.e.m. n = 9), not significantly different (P > 0.1) from that found by MRS (27 +/- 2.9%, n = 9, London, and 35 +/- 6.7, n = 14, Baltimore). In untreated RIF-1 tumours, pH was about 0.2 units higher than pHe (P < 0.01). 5-Fluorouracil (5FU) treatment (165 mg kg(-1)) caused no significant changes in either pHe or per cent extracellular volume. However significant increases in pH, 48 h after treatment (P < 0.01) correlated with decreased tumour size and improved bioenergetic status [NTP/inorganic phosphate (Pi) ratio]. This study shows the feasibility of an MR method (verified by a 'gold standard') for studying the effects of drug treatment on intra- and extracellular spaces and pH in solid tumours in vivo.
Bhujwalla
Z M
ZM
Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
McCoy
C L
CL
Glickson
J D
JD
Gillies
R J
RJ
Stubbs
M
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D009943:Organophosphorus Compounds; D010758:Phosphorus; D011437:Propylamines
D000964:Antimetabolites, Antineoplastic; D009943:Organophosphorus Compounds; D011437:Propylamines; C031116:dimethyl methylphosphonate; D010758:Phosphorus; D005472:Fluorouracil; C011649:3-aminopropylphosphonic acid