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: Y Pommier, J M Covey, D Kerrigan, J Markovits, R Pham
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 15 Issue 16 Pg. 6713-31 (Aug 25 1987) ISSN: 0305-1048 [Print] England
• PMID: 2819825 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Aminoacridines
• DNA, Viral
• Intercalating Agents
• Neoplasm Proteins
• Topoisomerase I Inhibitors
• Aminacrine
• Ethidium

Topics

• Aminacrine (analogs & derivatives, pharmacology)
• Aminoacridines (pharmacology)
• Animals
• DNA, Viral (drug effects)
• Ethidium (pharmacology)
• Intercalating Agents (pharmacology)
• Leukemia L1210 (enzymology)
• Mice
• Neoplasm Proteins (antagonists & inhibitors)
• Nucleic Acid Conformation (drug effects)
• Structure-Activity Relationship
• Topoisomerase I Inhibitors