title: DNA unwinding and inhibition of mouse leukemia L1210 DNA topoisomerase I by intercalators.
abstract: The DNA unwinding effects of some 9-aminoacridine derivatives were compared under reaction conditions that could be used to study drug-induced topoisomerase II inhibition. An assay was designed to determine drug-induced DNA unwinding by using L1210 topoisomerase I. 9-aminoacridines could be ranked by decreasing unwinding potency: compound C greater than or equal to 9-aminoacridine greater than o-AMSA greater than or equal to compound A greater than compound B greater than m-AMSA. Ethidium bromide was more potent than any of the 9-aminoacridines. This assay is a fast and simple method to compare DNA unwinding effects of intercalators. It led to the definition of a drug intrinsic unwinding constant (k). An additional finding was that all 9-aminoacridines and ethidium bromide inhibited L1210 topoisomerase I. Enzyme inhibition was detectable at low enzyme concentrations (less than or equal to 1 unit) and when the kinetics of topoisomerase I-mediated DNA relaxation was studied. Topoisomerase I inhibition was not associated with DNA swivelling or cleavage.
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
authors.forename: J M
authors.initials: JM
authors.lastname: Covey
authors.forename: D
authors.initials: D
authors.lastname: Kerrigan
authors.forename: J
authors.initials: J
authors.lastname: Markovits
authors.forename: R
authors.initials: R
authors.lastname: Pham
mesh_terms: D000585:Aminacrine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D004279:DNA, Viral / Q000187:drug effects; D004996:Ethidium / Q000494:pharmacology; D007364:Intercalating Agents / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000201:enzymology*; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009690:Nucleic Acid Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D000609:Aminoacridines; D004279:DNA, Viral; D007364:Intercalating Agents; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D000585:Aminacrine; D004996:Ethidium