P-31-MRS MEASUREMENTS OF EXTRACELLULAR PH OF TUMORS USING 3-AMINOPROPYLPHOSPHONATE

The extracellular pH (pH(ex)) of tumors is generally acidic. However, it is only recently that noninvasive magnetic resonance spectroscopic (MRS) measurements have determined that the intracellular pH (pH(in)) of tumor cells in situ is neutral or slightly alkaline compared with that of normal tissues. Thus cells in tumors maintain larger pH gradients than do cells in nontumor tissues. To date, measurements of pH(ex) in tumors have been made using microelectrodes, which preclude measurement of pH(ex) and pH(in) within the same preparation. In addition, microelectrodes are invasive and have the potential to alter the measured pH values. The present communication describes simultaneous measurement of pH(ex) and pH(in) in vitro in bioreactor culture and in vivo using P-31-MRS analyses of 3-aminopropylphosphonate (3-APP) and inorganic phosphate. In vitro results indicate that 3-APP is not toxic and that its resonant frequency is sensitive to pH and not significantly affected by temperature or ionic strength. Bioreactor experiments indicate that this compound is neither internalized nor metabolized by cells. Experiments in vivo indicate that 3-APP can be administered intraperitoneally and that RIF-1 tumors maintain a steady-state pH(in) of 7.25 and a pH(ex) of 6.66. These data have significance to basic tumor cell physiology and to the design of approaches to cancer chemotherapy and hyperthermic therapy, because both of these modalities exhibit pH sensitivity. It is also likely that these techniques will be applicable to localized MRS of other organ systems in vivo.