title: Selection of cancer chemopreventive agents based on inhibition of topoisomerase II activity.
abstract: The present study was undertaken to determine if in vitro inhibition of one or both of the two most dominant mammalian DNA topoisomerases (topos) is common among chemopreventive agents. To determine if an agent was a topo I inhibitor, we employed the DNA relaxation and nicking assays. For potential topo II inhibitors, we used the DNA unknotting and linearisation assays. 14 of 30 agents (47%) were ineffective in all four assays (IC(50) >100 microgram/ml), and 11 (37%) inhibited topo II catalytic activity. The sensitivity of the topo II assay was 63%, selectivity 93%, positive predictive value 91%, and total accuracy 77%. For chemopreventive efficacy, the positive predictive value of the unknotting assay was 92%, and the total accuracy was 60%. These data suggest that reduced topo II activity is a desirable property of many known chemopreventive agents. We conclude that the unknotting assay could be a valuable addition to the in vitro tests presently used to select chemopreventive agents.
authors.affiliation: Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago, 840 South Wood Street 60612, Chicago, IL, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Cho
authors.forename: J M
authors.initials: JM
authors.lastname: Pezzuto
authors.forename: J L
authors.initials: JL
authors.lastname: Bolton
authors.forename: V E
authors.initials: VE
authors.lastname: Steele
authors.forename: G J
authors.initials: GJ
authors.lastname: Kelloff
authors.forename: S K
authors.initials: SK
authors.lastname: Lee
authors.forename: A
authors.initials: A
authors.lastname: Constantinou
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism / Q000627:therapeutic use*; D006224:Cricetinae; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051381:Rats; D012680:Sensitivity and Specificity; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D016588:Anticarcinogenic Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors