INHIBITION OF DNA TOPOISOMERASE-II BY IMIDAZOACRIDINONES, NEW ANTINEOPLASTIC AGENTS WITH STRONG ACTIVITY AGAINST SOLID TUMORS

Imidazoacridinones are new antitumor compounds that exhibit strong ant itumor effect against solid tumors such as human colon and breast carc inomas. The mechanism of action of imidazoacridinones is unknown, alth ough a similarity in the chemical structure between active imidazoacri dinones and mitoxantrone suggests common cellular targets. We show tha t imidazoacridinones inhibit the catalytic activity of purified topois omerase II as determined by both relaxation and decatenation assays. A ll biologically active compounds stimulated the formation of cleavable complexes in vitro, whereas inactive compounds did not, The pattern o f DNA cleavage in SV40 DNA was similar to that obtained for 4'-(9-acri dinylamino)methanesulfon-m-aniside, particularly within the matrix-ass ociated region. Significant levels of DNA complexes were observed when DC-3F fibrosarcoma cells were treated with active compounds, whereas negligible amounts of these complexes were induced by inactive analogu es. DC-3F/9-OHE cells, which are resistant to other topoisomerase II i nhibitors, are 30-125-fold cross-resistant to active imidazoacridinone s. The resistance is associated with a reduction in the formation of D NA/protein complexes and is highest for compounds that are potent topo isomerase II inhibitors in vitro. Interestingly, the two most active d erivatives, C-1310 and C-1311, were equally cytotoxic toward fast-grow ing monolayer cultures and cells growing in three dimensions as multic ellular spheroids, which have a slower growth fraction. In contrast, 4 '-(9-acridinylamino)methanesulfon-m-aniside, mitoxantrone, and doxorub icin were more cytotoxic toward monolayer cultures. Taken together, th e results suggest that DNA topoisomerase II is a major cellular target of biologically active imidazoacridinones and that these drugs show b oth similarities and dissimilarities compared with classic topoisomera se II inhibitors.