Role of DNA intercalation in the inhibition of purified mouse leukemia (L1210) DNA topoisomerase II by 9-aminoacridines.
An attempt was made to analyze the mechanism by which 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) inhibits mammalian DNA topoisomerase II. The effects of various 9-aminoacridine derivatives differing by their DNA affinities and DNA sequence selectivity of binding were compared in the presence of purified mouse leukemia L1210 DNA topoisomerase II. No correlation was found between DNA unwinding and topoisomerase II inhibition. 9-Aminoacridine was inactive as a topoisomerase II inhibitor and o-AMSA was only weakly active. The location of L1210 topoisomerase II mediated DNA breaks produced in the absence or presence of 9-aminoacridines were studied in [32P]-end-labeled pBR 322 DNA. All 9-aminoacridines, even those differing by their DNA sequence selectivity of binding, produced similar DNA cleavage patterns. Most drug-induced topoisomerase II mediated DNA breaks appeared at sites that were already cleaved by the enzyme in the absence of drug. The present results suggest that 9-aminoacridines inhibit L1210 DNA topoisomerase II by interacting at or near enzyme-DNA complexes by some unknown DNA effect or by direct protein interaction.
Pommier
Y
Y
Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD 20892.
Covey
J
J
Kerrigan
D
D
Mattes
W
W
Markovits
J
J
Kohn
K W
KW
D000609:Aminoacridines / Q000494:pharmacology*; D000677:Amsacrine / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000032:analysis; D004249:DNA Damage; D007364:Intercalating Agents / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000201:enzymology*; D051379:Mice; D059005:Topoisomerase II Inhibitors
D000609:Aminoacridines; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D004247:DNA