ADP-RIBOSYLATION INHIBITORS INHIBIT CELLULAR RNA-SYNTHESIS BUT DO NOTAFFECT EXPRESSION OF MANGANOUS SUPEROXIDE-DISMUTASE OR HEAT-SHOCK PROTEIN-70 IN TUMOR-NECROSIS-FACTOR-ALPHA-SENSITIVE AND TUMOR-NECROSIS-FACTOR-ALPHA-RESISTANT TUMOR-CELLS

We have shown that the cytotoxic response of TNF-sensitive L929 cells and TNF-resistant EMT-6 cells to TNF-alpha can be modulated by ADP-rib osylation inhibitors independently of ADP-ribosylation rates, To explo re the possibility that these inhibitors modulate TNF cytotoxicity by interfering with cellular protective mechanisms, we evaluated their ef fects on general RNA synthesis and on mRNA expression of two proposed protective genes, manganous superoxide dismutase (MnSOD) and heat shoc k protein 70 (hsp70), We found that ADP-ribosylation inhibitors could inhibit general RNA synthesis in a dose-dependent fashion to a similar extent in both EMT-6 and L929 cells, although these inhibitors increa sed or decreased the sensitivity of the cells to TNF, respectively, In EMT-6 cells, combination of actinomycin D with these inhibitors furth er inhibited the RNA synthesis rate, and it actually decreased the TNF sensitivity of the EMT-6 cells, Furthermore, the expression of MnSOD or hsp70 was not regulated by these inhibitors, Thus, TNF resistance m ust depend on other mechanisms in addition to the expression of these protective genes.