DNA-SEQUENCE SELECTIVITY OF TOPOISOMERASES AND TOPOISOMERASE POISONS

Chemical agents able to interfere with DNA topoisomerases are widespre ad in nature, and some of them have clinical efficacy as antitumor or antibacterial drugs. Drugs which have as a target DNA topoisomerases c ould be divided into two categories: poisons and catalytic inhibitors. Classical topoisomerase poisons stimulate cleavage in a sequence-sele ctive manner, yielding drug-specific cleavage intensity pattern. The m echanisms of drug interaction with DNA topoisomerases, the DNA sequenc e selectivity of the action of topoisomerase II poisons and the identi fication of structural determinants of their activity have suggested t hat topoisomerase II poisons may fit into a specific pharmacophore, co nstituted by a planar ring system with DNA intercalation or intercalat ion-like properties, and protruding side chains interfering with the p rotein side of the covalent enzyme-DNA complex. The complete definitio n of the diverse pharmacophores of topoisomerase II poisons will certa inly be of value for the design of new agents directed to specific gen omic sites, and more effective in the treatment of human cancer. 0167- 4781/98/$ - see front matter (C) 1998 Elsevier Science B.V. All rights reserved.