DIFFERENTIATION OF U-937 PROMONOCYTIC CELLS BY ETOPOSIDE AND ICRF-193, 2 ANTITUMOR DNA TOPOISOMERASE-II INHIBITORS WITH DIFFERENT MECHANISMS OF ACTION

We have compared the action on U-937 human promonocytic leukemia cells of two DNA topoisomerase II inhibitors, namely the epipodophyllotoxin etoposide and the bisdioxopiperazine ICRF-193, One hour pulse-treatme nt with 3 mu M etoposide caused topoisomerase-associated, primary DNA breakage, which was rapidly followed by apoptosis, By contrast, these effects were not observed upon pulse-treatment with 6 mu M ICRF-193, H owever, continuous treatments with subcytotoxic concentrations of etop oside (0.15 mu M) and ICRF-193 (0.3 mu M) produced several similar eff ects, namely decreased cell proliferation, accumulation of cells at G( 2), increase in cell mass, and induction of differentiation. Under the se conditions, etoposide produced a biphasic activation of protein kin ase C, which consisted in an early transient activation (from hours 1 to 6) of the membrane-bound enzyme followed by a later activation (hou r 48) of the total, membrane-bound and cytosolic enzyme, By contrast, ICRF-193 only provoked a late activation (from hours 72 to 96) of the total enzyme, When used at differentiation-inducing concentrations, bo th topoisomerase inhibitors caused a great stimulation of AP-1 binding activity, with maximum value at hour 12 in etoposide-treated cells an d at hour 48 in ICRF-193-treated cells, By contrast, the binding activ ity of the NF-kappa B and EGR-1 transcription factors was little affec ted, It is concluded that topoisomerase II inhibitors may induce the d ifferentiation of promonocytic cells, independently of their capacity to cause DNA strand breaks, However, there are other effects, such as the early activation of protein kinase C, which are probably derived f rom the production of primary DNA breakage by some anti-topoisomerase drugs.