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Effects of Chemotherapy by 1,3-Bis(2-chloroethyl)-1-nitrosourea on Single-Quantum- and Triple-Quantum-filtered ²³Na and ³¹P Nuclear Magnetic Resonance of the Subcutaneously Implanted 9L Glioma¹

Department of Radiology, The University of Pennsylvania, Philadelphia, Pennsylvania 19104 [P. M. W., H. P., N. B.]; and Joint Program in Biomedical Engineering, The University of Texas, Arlington, Texas 19019 [P. M. W., N. B.]

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 ³¹P nuclear magnetic resonance (NMR) spectroscopy, total tissue sodium by single-quantum (SQ) ²³Na NMR spectroscopy, and intracellular sodium by triple-quantum-filtered (TQF) ²³Na NMR spectroscopy were studied in the s.c. 9L glioma. Animals were studied by NMR 2 days before therapy and 1 and 5 days after therapy. Destructive chemical analysis was also performed 5 days after therapy to validate the origin of changes in SQ and TQF ²³Na signals. One day after treatment, there was no significant difference between control and treated tumors in terms of tumor size or ²³Na and ³¹P spectral data. Five days after therapy, treated tumors had 28 ± 16% (P < 0.1) lower SQ ²³Na signal intensity, 46 ± 20% (P < 0.05) lower TQF ²³Na 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 intracellular pH compared with control tumors. No significant differences in TQF ²³Na relaxation times were seen between control and treated tumors at any time point. Destructive chemical analysis showed that the relative extracellular space of control and treated tumors was identical, but the treated tumors had 21 ± 8% (P < 0.05) lower total tissue Na⁺ concentration and 60 ± 24% (P < 0.05) lower intracellular Na⁺ concentration compared with the controls. The higher phosphocreatine:P_i and ATP:P_i ratios after 1,3-bis(2-chloroethyl)-1-nitrosourea treatment indicate improved bioenergetic status in the surviving tumor cells. The decrease in SQ and multiple-quantum-filtered ²³Na 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 concentration of Na⁺ by increasing the activity of Na⁺-K⁺-ATPase and decreasing the activity of Na⁺/H⁺. Although both ²³Na and ³¹P spectra were consistent with improved cellular metabolism in treated tumors, the ²³Na methods may be better suited for monitoring response to therapy because of higher signal:noise ratio and ease of imaging the single ²³Na resonance.

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