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Manipulation of Oxygen Radical-scavenging Capacity in Mice Alters Host Sensitivity to Tumor Necrosis Factor Toxicity but Does Not Interfere with Its Antitumor Efficacy

Surgery Branch [G. J. H., J. K. M., S. A. R.] and the Laboratory of Pathology [W. D. T.], National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and the Department of Critical Care Medicine, Children's National Medical Center, Washington, DC 20010 [G. J. H.]

The role of oxygen free radicals in the toxicity and antitumor effect of tumor necrosis factor was investigated in vivo. Treatment of non-tumor-bearing mice and mice bearing methylcholanthrene-induced sarcomas with bovine CuZn superoxide dismutase or recombinant human CuZn superoxide dismutase afforded significant protection to these mice from a subsequent challenge with recombinant human tumor necrosis factor (rhTNF). Pretreatment with superoxide dismutase increased survival rates, at 48 h after rhTNF injection, in non-tumor-bearing mice from 22 to 65% and in tumor-bearing mice from 25 to 79%. Protection from rhTNF toxicity was not associated with any reduction in the therapeutic efficacy of rhTNF against methylcholanthrene-induced sarcomas in either s.c. or visceral sites (e.g., cure rates in mice bearing s.c. tumors which were treated with rhTNF without or with superoxide dismutase pretreatment were 18 and 39%, respectively). Furthermore, the administration of L-buthionine-S,R-sulfoximine, an inhibitor of glutathione synthesis, to mice bearing s.c. tumors resulted in increased rhTNF toxicity but no improvement in therapeutic efficacy. Tumor necrosis factor toxicity is mediated by the release of oxygen free radicals, probably from activated neutrophils, but its antitumor effect in methylcholanthrene-induced sarcomas is not dependent on their generation.

¹ To whom requests for reprints should be addressed, at Division of Pediatric Critical Care Medicine, Georgetown University Children's Medical Center, 3800 Reservoir Rd. NW, Washington, DC 20007.

Received 11/ 3/89. Revised 2/26/90.

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