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Early metabolic response to tumor necrosis factor in mouse sarcoma: a phosphorus-31 nuclear magnetic resonance study
N Shine1, M A Palladino, J S Patton
1Magnetic Resonance Unit, Veterans Administration Medical Center, San Francisco, California 94121.
Abstract:
To investigate the effects of recombinant human tumor necrosis factor alpha (rHuTNF-alpha) 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 micrograms of rHuTNF-alpha 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-alpha could be due to either a primary action on tumor biochemistry or a secondary action produced by ischemia. These findings indicate that rHuTNF-alpha 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-alpha or other treatments in animal and human cancers.
Insights
Recombinant human tumor necrosis factor alpha (rHuTNF-alpha) rapidly alters cancer cell energy metabolism, depleting ATP and phosphocreatine. 31P NMR detected these changes, suggesting its utility in monitoring cancer treatments.
Area of Science:
- Biochemistry
- Oncology
- Medical Imaging
Background:
- Recombinant human tumor necrosis factor alpha (rHuTNF-alpha) is a cytokine with potential anti-cancer properties.
- Understanding its mechanism of action, particularly its effects on tumor metabolism, is crucial for therapeutic development.
Purpose of the Study:
- To investigate the impact of rHuTNF-alpha on high-energy phosphate metabolism in cancer cells.
- To assess the utility of 31P nuclear magnetic resonance (NMR) spectroscopy in detecting these metabolic changes.
Main Methods:
- 31P NMR spectroscopy was employed on a murine methylcholanthrene-induced sarcoma model.
- Spatially localized NMR techniques were used to differentiate tumor-specific metabolic changes.
- Metabolic alterations were correlated with histological findings of thrombosis and hemorrhage.
Main Results:
- Injection of rHuTNF-alpha led to rapid depletion of ATP and phosphocreatine within 90 minutes.
- An increase in inorganic phosphate was observed concurrently with ATP and phosphocreatine depletion.
- Metabolic changes were tumor-specific and mimicked those induced by acute tumor ischemia.
- These rapid metabolic effects were detectable by 31P NMR.
Conclusions:
- rHuTNF-alpha exerts a rapid onset of action on tumor high-energy phosphate metabolism.
- The observed metabolic changes may be mediated by direct biochemical effects or secondary ischemia.
- 31P NMR spectroscopy is a valuable tool for detecting early biochemical responses to rHuTNF-alpha and other cancer therapies in vivo.