Activation of programmed cell death by recombinant human tumor necrosis factor plus topoisomerase II-targeted drugs in L929 tumor cells.

The mechanism of death induced by recombinant human tumor necrosis factor (rHuTNF) in L929 tumor cells of C3H mice was investigated. Treatment with rHuTNF led to fragmentation of DNA into nucleosomal oligomers and to induction of the expression of TRPM-2, a programmed cell death-associated gene. Both events preceded cell death by several hours. Treatment with DNA topoisomerase II inhibitors accelerated both the rHuTNF-mediated DNA fragmentation and the elevation in TRPM-2 messenger RNA levels. These results suggest that rHuTNF exerts its cytotoxicity on L929 cells by activating programmed cell death, leading to apoptosis, and that topoisomerase II inhibitors enhance rHuTNF-mediated cytotoxicity by accelerating this process.