Selection of cancer chemopreventive agents based on inhibition of topoisomerase II activity

The present study was undertaken to determine if ill vitro inhibition of on e 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. 1 4 of 30 agents (47%) were ineffective in all four assays (IC50 > 100 mug/ml ), and 11 (37%) inhibited topo II catalytic activity. The sensitivity of th e topo II assay was 63%, selectivity 93%, positive predictive value 91%. an d total accuracy 77%. For chemopreventive efficacy, the positive predictive value of the unknotting assay was 92%, and the total accuracy was 60%. The se data suggest that reduced topo II activity is a desirable property of ma ny known chemopreventive agents. We conclude that the unknotting assay coul d be a valuable addition to the in vitro tests presently used to select che mopreventive agents. (C) 2000 Elsevier Science Ltd. All rights reserved.