The role of oxidant injury in tumor cell sensitivity to recombinant human tumor necrosis factor in vivo. Implications for mechanisms of action.
The intracellular glutathione levels of two human tumor lines and seven murine tumor lines were determined in order to investigate the role of oxidant injury in tumor cell sensitivity to human rTNF (rhTNF). Correlations were found between high intracellular glutathione levels and in vivo tumor resistance to rhTNF, and on the other hand, low glutathione levels and rhTNF sensitivity. The transplantable murine fibrosarcoma, Meth A, a TNF-sensitive line in vivo, was less sensitive to rhTNF and host toxicity was reduced when the hosts were pretreated with uric acid, a major reactive oxygen scavenger in humans and certain other primates. Conversely, pretreatment of the tumor-bearing hosts with DL-buthionine-(S,R)-sulfoximine, an inhibitor of GSH biosynthesis, resulted in an increased sensitivity of Meth A to rhTNF. This effect was not limited to tumor-bearing mice, as rats pretreated with diethyl maleate, a compound which irreversibly binds glutathione, were more sensitive to rhTNF toxicity than control rats. On the other hand, pretreatment with N-acetyl cysteine, an oxidant scavenger, reduced the toxicity of rhTNF treatment in rats. The data are consistent with the hypothesis that tumor cell sensitivity to rhTNF in vivo is dependent on its capacity to buffer oxidative attack. In addition, host toxicity is also related to the production of reactive oxygen species. Activated effector cells such as granulocytes and macrophages are hypothesized to produce most of this damage by their respiratory burst and oxidant release, although the direct action of rhTNF may also contribute to oxidative injury in vivo.
Zimmerman
R J
RJ
Department of Pharmacology, CETUS Corporation, Emeryville, CA 94608.
Marafino
B J
BJ
Chan
A
A
Landre
P
P
Winkelhake
J L
JL
D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D005260:Female; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008054:Lipid Peroxides / Q000633:toxicity; D008298:Maleates / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010100:Oxygen / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D005609:Free Radicals; D008054:Lipid Peroxides; D008298:Maleates; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C014476:diethyl maleate; D005978:Glutathione; D010100:Oxygen; D000111:Acetylcysteine