POTENTIATION OF TUMOR-NECROSIS-FACTOR INDUCED APOPTOSIS BY ONCONASE

Onconase (ONC) a ribonuclease from amphibian oocytes is cytostatic and cytotoxic to many human tumor lines, shows in vivo antitumor activity in mouse tumor models and is in Phase UI clinical trials. The mechani sm of antitumor activity of ONC is presumed to be due to its internali zation, degradation of intracellular RNA and suppression of protein sy nthesis. Since apoptosis triggered by TNF-alpha is known to be potenti ated by inhibitors of protein synthesis, we have hypothesized that it also may be potentiated by ONC. Indeed, preincubation of U-937 or HL-6 0 leukemic cells with 0.17 mu M ONC rendered them more sensitive to in duction of apoptosis by TNF-alpha or antibody to CD95 (Fas). The mecha nism by which ONC amplifies the effect of TNF-alpha may involve suppre ssion of induction of the survival genes whose expression is triggered by activation of NF kappa B by this factor.