Open AccessMenogaril, an Anthracycline Derivative, Inhibits DNA Topoisomerase II by Stabilizing Cleavable Complexes
Author(s) -
Ono Katsuhiro,
Ikegami Yoji,
Nishizawa Miwako,
Andoh Toshiwo
Publication year - 1992
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.1992.tb02016.x
Subject(s) - topoisomerase , kinetoplast , crithidia fasciculata , dna , anthracycline , etoposide , biology , mechanism of action , cleavage (geology) , biochemistry , crithidia , enzyme , microbiology and biotechnology , in vitro , genetics , protozoa , chemotherapy , paleontology , cancer , fracture (geology) , breast cancer
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 μM, which is comparable to that of etoposide. It does not, however, inhibit topoisomerase I activity at concentrations of up to 400 μM. Binding of topoisomerase II with DNA is not affected, but cleavable complex formation is stimulated by the drug. Cleavage site specificity differes 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.