Effects of two distamycin-ellipticine hybrid molecules on topoisomerase I and 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 capable 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 compounds distamycin and ellipticine. By contrast, the biscationic hybrid Distel (2+) exerts no significant effects on either topoisomerase I or II. The cytotoxic properties of the two drugs towards P388 leukaemic cells sensitive and resistant to camptothecin correlate with topoisomerase inhibitory properties but not with DNA-binding properties.
Riou
J F
JF
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, France.
Grondard
L
L
Naudin
A
A
Bailly
C
C
D000818:Animals; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000037:antagonists & inhibitors; D004214:Distamycins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004214:Distamycins; D004611:Ellipticines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C078726:Distel; C095173:distel(2+); D003850:Deoxyribonuclease I; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II