DIFFERENTIAL SENSITIVITIES OF RECOMBINANT HUMAN TOPOISOMERASE-II-ALPHA AND TOPOISOMERASE-II-BETA TO VARIOUS CLASSES OF TOPOISOMERASE-II INTERACTING AGENTS

A series of topoisomerase-interacting antitumour agents were tested fo r their ability to differentially inhibit the catalytic activity of ei ther topoisomerase (TOPO) II alpha or beta, as judged by a DNA decaten ation assay. The alpha form, relative to the beta isoform, proved 1 to 3 times more sensitive to nonintercalating complex-stabilizing TOPO I I-interacting agents (etoposide and derivatives) and up to 18 times mo re sensitive to non complex-stabilizing inhibitors of TOPO II ((+/-)-1 ,2-bis(3,5-dioxopiperazinyl-1-yl)propane [ICRF 159] and meso-2,3-bis(3 ,5-dioxopiperazine-1-yl)butane [ICRF 193]). However, the beta form of the enzyme appeared 1 to 3 times more sensitive to intercalating TOPO II-interacting agents (daunorubicin, aclarubicin and mitoxantrone). A possible implication of these data are that rumours preferentially exp ressing either the oc or the beta isoform may be differentially respon sive to various classes of TOPO II-interacting agents. BIOCHEM PHARMAC OL 56;4:503-507, 1998. (C) 1998 Elsevier Science Inc.