{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T12:14:52Z","timestamp":1769170492622,"version":"3.49.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2002,5,24]],"date-time":"2002-05-24T00:00:00Z","timestamp":1022198400000},"content-version":"vor","delay-in-days":143,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2002,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Merbarone is a catalytic inhibitor of topoisomerase II (topo II) that has been proposed to act primarily by blocking topo II\u2010mediated DNA cleavage without stabilizing DNA\u2013topo II\u2010cleavable complexes. In this study merbarone was used as a model compound to investigate the genotoxic effects of catalytic inhibitors of topo II. The clastogenic properties of merbarone were evaluated using in vitro and in vivo micronucleus (MN) assays combined with CREST staining. For the in vitro MN assay, ICRF\u2010187, a different type of catalytic inhibitor, and etoposide, a topo II poison, were used for comparison. Treatment of TK6 cells with all three of these drugs resulted in highly significant dose\u2010related increases in kinetochore\u2010lacking MN and, to a lesser extent, kinetochore\u2010containing MN. In addition, a good correlation between p53 accumulation and MN formation was seen in the drug\u2010treated cells. A mouse MN assay was performed to confirm that similar DNA\u2010damaging effects would occur in vivo. Bone marrow smears from merbarone\u2010treated B6C3F1 mice showed a dose\u2010related increase in micronucleated polychromatic erythrocytes with a mean of 26 MN per 1000 cells being seen at the 60 mg\/kg dose. Almost all MN lacked a kinetochore signal, indicating that merbarone was predominantly clastogenic under these conditions in vivo. The present study clearly shows that merbarone is genotoxic both in vitro and in vivo, and demonstrates the inaccuracy of earlier statements that merbarone and other catalytic inhibitors block the enzymatic activity of topo II without damaging DNA. Environ. Mol. Mutagen. 39:348\u2013356, 2002. \u00a9 2002 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/em.10072","type":"journal-article","created":{"date-parts":[[2002,10,6]],"date-time":"2002-10-06T12:21:52Z","timestamp":1033906912000},"page":"348-356","source":"Crossref","is-referenced-by-count":58,"title":["Catalytic inhibitors of topoisomerase II are DNA\u2010damaging agents: induction of chromosomal damage by merbarone and ICRF\u2010187"],"prefix":"10.1002","volume":"39","author":[{"given":"Ling","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Eastmond","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2002,5,24]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/10.4.343"},{"key":"e_1_2_1_3_1","first-page":"83","article-title":"Topoisomerase II inhibitors affect entry into mitosis and chromosome condensation in BHK cells","volume":"7","author":"Anderson H","year":"1996","journal-title":"Cell Growth Differ"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0309-1651(05)80016-5"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-9084(98)80006-0"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4781(98)00133-X"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4781(98)00137-7"},{"key":"e_1_2_1_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4274(00)00192-2"},{"key":"e_1_2_1_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/326414a0"},{"key":"e_1_2_1_10_1","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0165-6147(97)90658-1","article-title":"A protein\u2010mediated mechanism for the DNA sequence\u2010specific action of topoisomerase II poisons","volume":"18","author":"Capranico G","year":"1997","journal-title":"Trends Pharmacol Sci"},{"key":"e_1_2_1_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/9.6.563"},{"key":"e_1_2_1_12_1","first-page":"1509","article-title":"Differences in inhibition of chromosome separation and G2 arrest by DNA topoisomerase II inhibitors merbarone and VM\u201026","volume":"55","author":"Chen M","year":"1995","journal-title":"Cancer Res"},{"key":"e_1_2_1_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400339"},{"key":"e_1_2_1_14_1","doi-asserted-by":"publisher","DOI":"10.1159\/000134517"},{"key":"e_1_2_1_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(85)90368-5"},{"key":"e_1_2_1_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-419X(89)90041-3"},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/372467a0"},{"key":"e_1_2_1_18_1","first-page":"2578","article-title":"In vitro and intracellular inhibition of topoisomerase II by the antitumor agent merbarone","volume":"49","author":"Drake FH","year":"1989","journal-title":"Cancer Res"},{"key":"e_1_2_1_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1218(89)90079-7"},{"key":"e_1_2_1_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.2850130104"},{"key":"e_1_2_1_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/14.6.605"},{"key":"e_1_2_1_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.28.17643"},{"key":"e_1_2_1_23_1","first-page":"1042","article-title":"Cell cycle progression and chromosome segregation in mammalian cells cultured in the presence of the topoisomerase II inhibitors ICRF\u2010187 [(+)\u20101,2\u2010bis(3,5\u2010dioxopiperazinyl\u20101\u2010yl)propane; 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