Inhibition of DNA topoisomerase II by imidazoacridinones, new antineoplastic agents with strong activity against solid tumors.
Imidazoacridinones are new antitumor compounds that exhibit strong antitumor effect against solid tumors such as human colon and breast carcinomas. The mechanism of action of imidazoacridinones is unknown, although a similarity in the chemical structure between active imidazoacridinones and mitoxantrone suggests common cellular targets. We show that imidazoacridinones inhibit the catalytic activity of purified topoisomerase II as determined by both relaxation and decatenation assays. All biologically active compounds stimulated the formation of cleavable complexes in vitro, whereas inactive compounds did not. The pattern of DNA cleavage in SV40 DNA was similar to that obtained for 4'-(9-acridinylamino)methane-sulfon-m-aniside, particularly within the matrix-associated 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 analogues. DC-3F/9-OHE cells, which are resistant to other topoisomerase II inhibitors, are 30-125-fold cross-resistant to active imidazoacridinones. The resistance is associated with a reduction in the formation of DNA/protein complexes and is highest for compounds that are potent topoisomerase II inhibitors in vitro. Interestingly, the two most active derivatives, C-1310 and C-1311, were equally cytotoxic toward fast-growing monolayer cultures and cells growing in three dimensions as multicellular spheroids, which have a slower growth fraction. In contrast, 4'-(9-acridinylamino)methanesulfon-m-aniside, mitoxantrone, and doxorubicin were more cytotoxic toward monolayer cultures. Taken together, the results suggest that DNA topoisomerase II is a major cellular target of biologically active imidazoacridinones and that these drugs show both similarities and dissimilarities compared with classic topoisomerase II inhibitors.
Skladanowski
A
A
Department of Structural Biology and Pharmacology, CNRS, URA 147 Institut Gustave-Roussy, Villejuif, France.
Plisov
S Y
SY
Konopa
J
J
Larsen
A K
AK
D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003421:Crithidia; D004249:DNA Damage; D004270:DNA, Circular / Q000737:chemistry; D004279:DNA, Viral / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D009593:Nitroimidazoles / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000609:Aminoacridines; D000970:Antineoplastic Agents; D004270:DNA, Circular; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D009593:Nitroimidazoles; D059005:Topoisomerase II Inhibitors