MODULATION OF TOPOISOMERASE ACTIVITIES BY TUMOR-NECROSIS-FACTOR

A number of chemotherapeutic agents which inhibit the DNA topoisomeras es markedly potentiate cell death mediated by tumor necrosis factor, s uggesting a role for these enzymes in the TNF cytotoxic mechanism. To investigate this possibility, topoisomerase I and II activities were a ssayed following TNF addition to murine L929 cells. Topoisomerase I an d II activities increased within 15 min of TNF addition and returned t o baseline levels within 1 and 2 hr, respectively. The increases in bo th topoisomerase activities were blocked by H-7 (but not H-8) and simi lar increases were seen following PMA addition. However, concentration s of H-7 which blocked the increased topoisomerase activities had no e ffect on TNF cytotoxicity nor on the enhancement of TNF cytotoxicity b y topoisomerase inhibitors. Thus, in these cells topoisomerase activit ies are directly modified by TNF during the initial phases of a cytoto xic response. However, neither TNF cytotoxicity nor the enhancement of TNF cytotoxicity by topoisomerase inhibitors appears to require the T NF-mediated increases in topoisomerase activities. (C) 1995 Academic P ress,Inc.