Menogaril, an anthracycline derivative, inhibits DNA topoisomerase II by stabilizing cleavable complexes

Menogaril, an anthracycline derivative, has been shown to possess antitumor activity in experimental animal systems, and is now under phase II clinical studies. However, its mechanism of action has not been elucidated. We have found that it inhibits the decatenation activity of purified DNA topoisomerase II using kinetoplast DNA from Crithidia fasciculata, its IC50 being 10 microM, which is comparable to that of etoposide. It does not, however, inhibit topoisomerase I activity at concentrations of up to 400 microM. Binding of topoisomerase II with DNA is not affected, but cleavable complex formation is stimulated by the drug. Cleavage site specificity differs from that of 4'-(9-acridinylamino)methanesulfon-m-anisidide. Menogaril was shown to possess a weak double-helix unwinding activity. These findings allow us to classify menogaril as a cleavable complex-stabilizing topoisomerase II inhibitor.