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Selective Depletion of Tumor ATP by 2-Deoxyglucose and Insulin, Detected by ³¹P Magnetic Resonance Spectroscopy¹

Magnetic Resonance Unit [G. S. K., J. T., A. S., M. W. W.], Surgical Metabolism Laboratory [J. M. A., A. S.], and Department of Surgery [J. M. A., A. S.], Veterans Administration Medical Center, and Departments of Radiology [G. S. K., M. W. W.], Medicine [M. W. W.], and Surgery [J. M. A.], University of California, San Francisco, California 94121

The purpose of this study was to investigate whether substrate deprivation acutely and selectively decreases ATP concentrations in an experimental sarcoma. Two methods of substrate deprivation were examined: glycolysis was inhibited using 2-deoxyglucose (2DG), and plasma substrate levels were reduced using insulin. The effects of treatment on tumor ATP, inorganic phosphate, and pH were studied by ³¹P nuclear magnetic resonance spectroscopy. 2DG (2 g/kg) was administered i.p. to rats bearing s.c. methylcholanthrene-induced sarcomas. Inhibition of glycolysis by 2DG caused a 52 ± 13% (SE) decrease in the tumor ATP to inorganic phosphate ratio, associated with a decrease in pH of 0.38 ± 0.10 unit. The same dose of 2DG caused no significant change in the ratio of phosphocreatine to ATP in brain. Insulin (125 units/kg, i.p.) caused a 68% decline in plasma glucose and a 71% decline in betahy-droxybutyrate compared to saline-treated animals. Concomitantly, ³¹P nuclear magnetic resonance spectroscopy detected a 48 ± 13% decrease in sarcoma ATP, with a reciprocal elevation of inorganic phosphate in insulin-treated animals. In contrast, the brain phosphocratine/ATP ratio was unaffected by insulin. These results suggest that large tumors are acutely sensitive to inhibition of glycolysis and reductions in plasma levels of substrates for oxidative phosphorylation and glycolysis, while the brain is unaffected. In addition, this work provides support for the use of ³¹P nuclear magnetic resonance spectroscopy to monitor tumor response to therapy.

¹ This work was supported in part by NIH Grant RO1 PKDK33-293-06, and the Department of Veterans Affairs Medical Research Service. G. S. K. was supported in part by National Research Service Award F32 AM07770-02.

² To whom requests for reprints should be addressed, at: Department of Radiology, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637.

Received 4/ 1/91. Accepted 10/16/91.

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