JLE

Bulletin du Cancer

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Cytotoxicity and interaction with topoisomerase II of amsacrine derivatives: influence of the 1’ substituent on the aniline moiety Volume 84, issue 10, Octobre 1997

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Amsacrine is an intercalating planar polycyclic aromatic molecule that displays antitumor activity. The cytotoxicity of this compound is related to its interaction with topoisomerase II. The substituent at position 1’ on the aniline is thought to be essential to the formation of the topoisomerase II-DNA cleavable complex and hence the cytotoxicity of the drug. The influence of three substituents at position 1’ on the modulation of the activity of topoisomerase II was investigated. The following observations emerge from our structure-activity relationship study: i) the effects of the drugs on topoisomerase II-mediated DNA cleavage in vitro are correlated with the results of the cyto-toxicity assays performed with cells sensitive (DC-3F) and resistant to topoisomerase II inhibitors (DC-3F/9-OH-E); ii) depending on the nature of the 1’ substituent of the drugs, the restoration of a normal topoisomerase II catalytic activity in resistant DC-3F/9-OH-E cells transfected with a plasmid carrying a wild type topoisomerase II cDNA (hTOP2) either does not modify the susceptibility of the cells to the drug or partially reverse the resistance phenotype. The molecular and cellular studies reveal that topoisomerase II is implicated in the cytotoxicity of amsacrine and confirm that the substituent at position 1’ on the anilino ring of amsacrine governs the interaction with topoisomerase II.