Abstract
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.
Highlights
Determination of accurate metabolite concentrations is essential to elucidate tumour biochemistry and its relationship to underlying tissue physiology
We demonstrate that this can be accomplished by 5IP-magnetic resonance spectroscopy (MRS) using dimethyl methylphosphonate (DMMP) and 3aminopropylphosphonate (3-APP) as markers for total and extracellular water spaces respectively
DMMP is distributed among all the water spaces. whereas 3-APP accesses only the extracellular compartment: both compounds are chemically inert and non-toxic and are. . suitable as compartmental volume indicators
Summary
Determination of accurate metabolite concentrations is essential to elucidate tumour biochemistry and its relationship to underlying tissue physiology. We have monitored changes in pH and pHe of RIF-1 tumours following treatment with 5FIT. Whereas the fractional volume measurements were made by both the MRS and radiolabelling method in London using separate cohorts of tumours.
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