EFFECTS OF 2 DISTAMYCIN-ELLIPTICINE HYBRID MOLECULES ON TOPOISOMERASE-I AND TOPOISOMERASE-II MEDIATED DNA CLEAVAGE - RELATION TO CYTOTOXICITY

Two distamycin-ellipticine conjugates were examined for their ability to modulate topoisomerase I and topoisomerase II-DNA cleavable complex formation in vitro. Hybrid molecules Distel (1+) and Distel (2+) both contain a DNA-intercalating chromophore and a tris-pyrrole element ca pable of binding within the minor groove of DNA. The two drugs differ only in the nature of the side chain attached to the distamycin moiety . The monocationic hybrid Distel (1+) is a dual topoisomerase I and II inhibitor with characteristics differing from those of the parent com pounds distamycin and ellipticine. By contrast, the biscationic hybrid Distel (2+) exerts no significant effects on either topoisomerase I o r II. The cytotoxic properties of the two drugs towards P388 leukaemic cells sensitive and resistant to camptothecin correlate with topoisom erase inhibitory properties but not with DNA-binding properties.