Early metabolic response to tumor necrosis factor in mouse sarcoma: a phosphorus-31 nuclear magnetic resonance study.

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.

[1]  T. Espevik,et al.  Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha , 1987, The Journal of experimental medicine.

[2]  B. Aggarwal,et al.  Characterization of the antitumor activities of human tumor necrosis factor-alpha and the comparison with other cytokines: induction of tumor-specific immunity. , 1987, Journal of immunology.

[3]  B. Beutler,et al.  Cachectin: more than a tumor necrosis factor. , 1987, The New England journal of medicine.

[4]  J. D. Albert,et al.  Shock and tissue injury induced by recombinant human cachectin. , 1986, Science.

[5]  J. Gamble,et al.  Stimulation of neutrophils by tumor necrosis factor. , 1986, Journal of immunology.

[6]  L. Chess,et al.  Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1 , 1986, The Journal of experimental medicine.

[7]  B. Beutler,et al.  Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1 , 1986, The Journal of experimental medicine.

[8]  J. Gamble,et al.  Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[9]  L. Old,et al.  Tumor necrosis factor (TNF). , 1985, Science.

[10]  B. Aggarwal,et al.  Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. , 1985, Journal of immunology.

[11]  D. T. Pegg,et al.  Theoretical description of depth pulse sequences, on and off resonance, including improvements and extensions thereof , 1985, Magnetic resonance in medicine.

[12]  T. Ng,et al.  Application ofin vivo NMR spectroscopy to cancer , 1984, Magnetic resonance in medicine.

[13]  Bharat B. Aggarwal,et al.  Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin , 1984, Nature.

[14]  B. Aggarwal,et al.  Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity , 1984, Nature.

[15]  L. Old,et al.  Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[16]  T. Ng,et al.  In vivo31P NMR study of the metabolism of murine mammary 16/C adenocarcinoma and its response to chemotherapy, x-radiation, and hyperthermia , 1983 .

[17]  Jerry D. Glickson,et al.  31P NMR spectroscopy of in vivo tumors , 1982 .

[18]  G. Striker,et al.  Neutrophil-mediated endothelial injury in vitro mechanisms of cell detachment. , 1981, The Journal of clinical investigation.