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.