CYTOTOXICITY AND INTERACTION WITH TOPOISO MERASE-II OF AMSACRINE DERIVATIVES - INFLUENCE OF THE 1'-SUBSTITUENT ON THE ANILINE MOIETY

Amsacrine is an intercalating planar polycyclic aromatic molecule that displays antitumor activity. The cytotoxicity of this compound is rel ated to its interaction with topoisomerase II. The substituent at posi tion 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 fo llowing observations emerge from our structure-activity relationship s tudy: i) the effects of the drugs on topoisomerase II-mediated DNA cle avage in vitro are correlated with the results of the cytotoxicity ass ays performed with cells sensitive (DC-3F) and resistant to topoisomer ase 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 alpha catalytic activity in resistant DC-3F/3-OH-E cells transfecte d with a plasmid carrying a wild type topoisomerase II alpha cDNA (hTO P2) either doer not modify the susceptibility of the cells to the drug or partially reverse the resistance phenotype. The molecular and cell ular studies reveal that topoisomerase II alpha is implicated in the c ytotoxicity of amsacrine and confirm that the substituent at position 1' on the anilino ring of amsacrine governs the interaction with topoi somerase II.