INHIBITION OF TOPOISOMERASE-II BY A NOVEL ANTITUMOR CYCLIC DEPSIPEPTIDE, BE-22179

BE-22179, a novel cyclic depsipeptide antibiotic having two 3-hydroxyq uinoline moieties, inhibited the DNA-relaxing activity of L1210 topois omerase II completely at 0.08 mu M This effect was far stronger than t hat of VP-16. However, it did not show any marked effect on topoisomer ase II-mediated DIVA cleavage, BE-22179 was ineffective in inhibiting the DNA relaxation by topoisomerase I at concentrations up to 10 mu M, but showed DNA-intercalating ability (DNA unwinding) at 30 mu M. The structure of BE-22179 is quite novel for a topoisomerase II inhibitor. Echinomycin, a quinoxaline antibiotic structurally related to BE-2217 9, interfered with DNA relaxation by topoisomerase II, though the effe ct was not due to inhibition of the catalytic activity of topoisomeras e II but to conformational change of DNA based on its intercalation in to DNA. Therefore, the potent inhibitory activity on topoisomerase II might not be a common activity of quinoxaline antibiotics, but might r ather be specific to BE-22179. BE-22179 prevented DNA synthesis as wel l as RNA synthesis in L1210 cells and inhibited the growth of the cell s. However, it remains unclear to what extent the topoisomerase II inh ibition was responsible for the cytotoxicity of BE-22179.