Abstract
A novel benzophenazine derivative, NC-190, is a potent antitumor compound. NC-190 has been shown to inhibit the DNA strand-passing activity of DNA topoisomerase II. We investigated further the mode of action of NC-190 against DNA topoisomerase II and DNA fragmentation. NC-190 inhibited the decatenation activity of purified topoisomerase II, but had only a weak inhibitory effect against topoisomerase I. A topoisomerase II-dependent DNA cleavage assay showed that NC-190 inhibited the enzyme activity by stabilizing a topoisomerase II–DNA cleavable complex. NC-190 induced growth inhibition, protein-linked DNA breaks, and DNA fragmentation in cultured HL-60 cells in a dose-dependent manner. These activities of NC-190 in HL-60 cells were comparable to those of etoposide (VP-16). These results demonstrate a good correlation among growth inhibition, topoisomerase II-dependent DNA cleavage, and DNA fragmentation induced by NC-190. A DNA unwinding assay showed that NC-190 had intercalating activity, but its activity appeared to be weaker than those of ethidium bromide and adriamycin. These results indicate that the mechanism by which NC-190 exhibits antitumor activity may be the inhibition of topoisomerase II.
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Received: 23 September 1994/Accepted: 2 August 1995
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Yamagishi, T., Nakaike, S., Ikeda, T. et al. A novel antitumor compound, NC-190, induces topoisomerase II-dependent DNA cleavage and DNA fragmentation. Cancer Chemother Pharmacol 38, 29–34 (1996). https://doi.org/10.1007/s002800050443
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DOI: https://doi.org/10.1007/s002800050443