Toxicity of tumor necrosis factors synergistic with γ-interferon and can be reduced with cyclooxygenase inhibitors

J. E. Talmadge, O. Bowersox, H. Tribble, S. H. Lee, H. M. Shepard, D. Liggitt

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

In recent studies, we have demonstrated that recombinant human tumor necrosis factor (rH TNF), as a single agent, has only minimal therapeutic activity for the treatment of metastatic disease, but when combined with recombinant murine γ-interferon (rM γ-IFN), we observed significantly more therapeutic activity than when either agent was administered alone. However, this combination also resulted in increased toxicity. Thus, we undertook a systematic toxicologic study of rH TNF alone or in combination with rM γ-IFN. Briefly, the toxicity was similar to the generalized Shwartzman's reaction seen during endotoxin shock, with multifocal microthrombi and ischemic necrosis as sequelae. Lesions were observed in the lungs, liver, gastrointestinal tract (preferentially in the duodenum and cecum), testes or uterus, and bone marrow. Our results suggest that TNF (either directly administered or induced in situ) and its induction of arachidonic acid metabolites form one element of toxicity in this model. This conclusion is supported by studies revealing that the toxicity of rH TNF in combination with rM γ-IFN can be reduced by inhibitors of the cycloxygenase/lipoxygenase pathway.

Original languageEnglish (US)
Pages (from-to)410-425
Number of pages16
JournalAmerican Journal of Pathology
Volume128
Issue number3
StatePublished - Jan 1 1987

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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