Effects of chemotherapy by 1,3-bis(2-chloroethyl)-1-nitrosourea on single-quantum- and triple-quantum-filtered Na-23 and P-31 nuclear magnetic resonance of the subcutaneously implanted 9L glioma

The effects of chemotherapy [25 mg/kg 1,3-bis(2-chloroethyl)-1-nitrosourea administered with a single i.p. injection] on cellular energetics by P-31 n uclear magnetic resonance (NMR) spectroscopy, total tissue sodium by single -quantum (SQ) Na-23 NMR spectroscopy, and intracellular sodium by triple-qu antum-filtered (TQF) Na-23 NMR spectroscopy were studied in the s.c. 9L gli oma. Animals were studied by NMR 2 days before therapy and 1 and 5 days aft er therapy. Destructive chemical analysis was also performed 5 days after t herapy to validate the origin of changes in SQ and TQF Na-23 signals. One d ay after treatment, there was no significant difference between control and treated tumors in terms of tumor size or Na-23 and P-31 spectral data. Fiv e days after therapy, treated tumors had 28 +/- 16% (P < 0.1) lower SQ Na-2 3 signal intensity, 46 +/- 20% (P < 0.05) lower TQF Na-23 signal intensity, 125 +/- 51% (P < 0.05) higher ATP:P-i ratio, 186 +/- 69% (P < 0.05) higher phosphocreatine:P-i ratio, and 0.17 +/- 0.06 pH units (P < 0.05) higher in tracellular pH compared with control tumors. No significant differences in TQF Na-23 relaxation times were seen between control and treated tumors at any time point. Destructive chemical analysis showed that the relative extr acellular space of control and treated tumors was identical, but the treate d tumors had 21 +/- 8% (P < 0.05) lower total tissue Na+ concentration and 60 +/- 24% (P < 0.05) lower intracellular Na+ concentration compared with t he controls. The higher phosphocreatine:P-i and ATP:P-i ratios after 15-bis (2-chloroethyl)-1-nitrosourea treatment indicate improved bioenergetic stat us in the surviving tumor cells. The decrease in SQ and multiple-quantum-fi ltered Na-23 signal intensity was largely attributable to a decrease in Na- i(+) because the treatment did not change the relative extracellular space. The improved energy metabolism could decrease the intracellular concentrat ion of Na+ by increasing the activity of Na+-K+-ATPase and decreasing the a ctivity of Na+/H+. Although both Na-23 and P-31 spectra were consistent wit h improved cellular metabolism in treated tumors, the Na-23 methods may be better suited for monitoring response to therapy because of higher signal:n oise ratio and ease of imaging the single Na-23 resonance.