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Intracellular Hydroxyl Radical Production Induced by Recombinant Human Tumor Necrosis Factor and Its Implication in the Killing of Tumor Cells in Vitro

Department of Internal Medicine (Section 4), Sapporo Medical College, South-1, West-16, Chuo-ku, Sapporo, 060, Japan

This study investigated the effect of recombinant human tumor necrosis factor (rhTNF) on hydroxyl radical production by established cell lines in vitro, and its implication in the killing of tumor cells by rhTNF. During incubation of TNF sensitive mouse tumorigenic fibroblast L-M cells (2 x 10⁷ cells) in the presence of rhTNF (100 U), hydroxyl radical production as detected by the evolution of methane gas from dimethyl sulfoxide increased gradually, at 18 h reaching 1.8 times that in the absence of rhTNF. This increase was dependent on the concentration of rhTNF and was effectively prevented by the simultaneous addition of anti-rhTNF monoclonal antibody III 2F3, which inhibited both the binding of rhTNF to its receptor and the cytotoxic activity of rhTNF. The addition of iron chelator 2,2'-bipyridine, which inhibits iron-catalized Fenton reaction and so inhibits hydroxyl radical generation, suppressed both the increase of hydroxyl radical production and the cytotoxicity induced by rhTNF. A similar increase in hydroxyl radical production in the presence of rhTNF was also detected with TNF-sensitive human myosarcoma-derived KYM cells, but no such increase was detected with TNF insensitive human embryonic lung fibroblast HEL cells.

The results show that rhTNF induces increased hydroxyl radical production in TNF-sensitive cells, and suggest that this plays an important role in the mechanism of tumor cell killing by rhTNF.

Received 7/12/88. Revised 10/27/88. Accepted 12/13/88.

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