To investigate the effects of recombinant human tumor necrosis factor α (rHuTNF-α) 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-α 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-α could be due to either a primary action on tumor biochemistry or a secondary action produced by ischemia. These findings indicate that rHuTNF-α 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-α or other treatments in animal and human cancers.
This work was supported in part by NIH Grant RO1 AM 33 923 and the Veterans Administration Medical Research Services.