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 t hat of normal tissues. Thus cells in tumors maintain larger pH gradien ts than do cells in nontumor tissues. To date, measurements of pH(ex) in tumors have been made using microelectrodes, which preclude measure ment of pH(ex) and pH(in) within the same preparation. In addition, mi croelectrodes are invasive and have the potential to alter the measure d pH values. The present communication describes simultaneous measurem ent of pH(ex) and pH(in) in vitro in bioreactor culture and in vivo us ing P-31-MRS analyses of 3-aminopropylphosphonate (3-APP) and inorgani c phosphate. In vitro results indicate that 3-APP is not toxic and tha t its resonant frequency is sensitive to pH and not significantly affe cted 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 intraperit oneally and that RIF-1 tumors maintain a steady-state pH(in) of 7.25 a nd 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 sens itivity. It is also likely that these techniques will be applicable to localized MRS of other organ systems in vivo.