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Early Metabolic Response to Tumor Necrosis Factor in Mouse Sarcoma: A Phosphorus-31 Nuclear Magnetic Resonance Study¹

Magnetic Resonance Unit [N.S., G.S.K., G.B.M., M.W.W.] and the Division of Oncology [A.J.], Veterans Administration Medical Center, San Franscisco, California 94121; Departments of Medicine [N.S., G.S.K.], Radiology [G.S.K., M.W.W.], and Pharmaceutical Chemistry [G.B.M.], University of California, San Fracisco, California 94143; and the Department of Molecular Immunology, Genentech Corporation [M.A.P., J.S.P.], South San Francisco, California 94080.

To investigate the effects of recombinant human tumor necrosis factor (rHuTNF-) on high-energy phosphate metabolism of cancer cells, ³¹P nuclear magnetic resonance (NMR) studies were performed on a murine methylcholanthrene-induced sarcoma. Injection of 15 µg of rHuTNF- caused progressive depletion of ATP and phosphocreatine within 90 min, together with an increase in inorganic phosphate. Metabolic changes were correlated with the early histological appearance of thrombosis and hemorrhage. A spatially localized NMR technique demonstrated that these changes were specific for the tumor. Acute ischemia of the tumor produced similar metabolic changes; thus the metabolic effects of rHuTNF- could be due to either a primary action on tumor biochemistry or a secondary action produced by ischemia. These findings indicate that rHuTNF- has a very rapid onset of action, which can be detected by ³¹P NMR. Furthermore, the results suggest that ³¹P NMR spectroscopy will be extremely useful for detecting early biochemical changes produced by rHuTNF- or other treatments in animal and human cancers.

¹ This work was supported in part by NIH Grant RO1 AM 33 923 and the Veterans Administration Medical Research Services.

² Present address: Medical Research Institute, San Francisco, CA.

³ To whom requests for reprints should be addressed, at Magnetic Resonance Unit (11D), VA Medical Center, 4150 Clement St., San Francisco, CA 94121.

Received 6/14/88. Revised 11/17/88. Accepted 1/10/89.