INHIBITION OF HUMAN TOPOISOMERASE-II BY ANTINEOPLASTIC BENZAZOLO[3,2-A]QUINOLINIUM CHLORIDES

Previously we reported [20] that there is no correlation between the c ytotoxic activity of four new structural analogs of the antitumor DNA intercalator 3-nitrobenzothiazolo [3,2-a]quinolinium chloride (NBQ-2) and their interaction with DNA. In the present study, we present evide nce suggesting that the molecular basis for the anti-proliferative act ivity of these drugs is the inhibition of topoisomerase II. The NBQ-2 derivatives inhibited the relaxation of supercoiled DNA plasmid pRYG m ediated by purified human topoisomerase II. Inhibition of the decatena tion of kinetoplast DNA mediated by partially purified topoisomerase I I extracted from the human histiocytic lymphoma U937 (a cell line prev iously shown to be sensitive to the drugs) was also caused by these dr ugs. The potency of the benzazolo[3,2-a] quinolinium drugs against top oisomerase II in vitro was the following: 7-(1-propenyl)-3-nitrobenzim idazolo[3,2-a] chloride (NBQ-59) > 4-chlorobenzothiazolo[3,2-a]quinoli nium chloride (NBQ-76) > 7-ethyl-3-nitrobenzimidazolo[3,2-a]quinoliniu m chloride (NBQ-48) > 7-benzyl-3-nitrobenzimidazolol[3,2-a]quinolinium chloride (NBQ-38). This rank of potency for topoisomerase II inhibiti on con-elated very well with the cytotoxicity elicited by these drugs. Furthermore, significant levels of topoisomerase II/DNA cleavage comp lex induced by these drugs in vivo were detected when U937 cells were treated with NBQ-59 and NBQ-76 whereas NBQ-38 and NBQ-48 produced negl igible amounts of the cleavage complex. Our results strongly suggest t hat topoisomerase II is the major cellular target of this family of co mpounds.