Synergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II.

Recombinant human tumor necrosis factor (rHTNF) alone had no effect on L929 tumor cells at 100 units/ml for 20 h of continuous exposure. However, under the same conditions, rHTNF markedly enhanced the cytotoxicity of Adriamycin, actinomycin D, 4'-(9-acridinylamino)-methanesulfon-m-anisidide, teniposide (VM 26), and etoposide (VP 16), all targeted at DNA topoisomerase II. The rHTNF had a minimally enhancing effect on the cytotoxicity of bleomycin, hydroxyurea, and 1-beta-D-arabinofuranosylcytosine and no effect on the cytotoxicity of cis-platinum, mitomycin C, vincristine, and vinblastine, all chemotherapeutic drugs with dose-related cytotoxic effects on L929 cells but mechanisms of action which do not appear to involve topoisomerase II. Treatment with rHTNF first and then topoisomerase-targeted drugs yielded no enhanced cytotoxicity, whereas pretreatment with drug followed by rHTNF yielded marked enhancement of cytotoxicity. Topoisomerases have previously been implicated in cell kill phenomena following treatment with certain chemotherapeutic agents [K.M. Tewey, et al., Science (Wash. DC), 226:466-468, 1984]. The data suggest that the lethality to the cell from topoisomerase-targeted drug treatment is increased by rHTNF in vitro. We suggest that rHTNF may be a useful adjuvant to this class of drugs which has well-known antitumor activity.