Further evidence that the radioprotective aminothiol, WR-1065, catalytically inactivates mammalian topoisomerase II

It has recently been proposed that the thiol form of the cytoprotective dru g amifostine that is designated WR-1065 [2-((aminopropyl)amino)ethanethiol] exerts its cytoprotective effects in part via a catalytic inhibition of DN A topoisomerase II (topo II) alpha. This in turn leads to the subsequent ac cumulation of cells in G(2) phase and a prolongation of the cell cycle. We have used a Chinese hamster V79 cell-based micronucleus assay to further ev aluate this hypothesis, It is demonstrated that WR-1065 strongly inhibits t he clastogenesis of the topo ZI poisons etoposide and clinafloxacin at clin ically attained exposure levels while having no effect on clastogenesis ind uced by topo II-noninteractive chemicals. These findings are consistent wit h the hypothesis that WR-1065 is a catalytic inhibitor of topo II in mammal ian cells. These studies also suggest that WR-1065 might be expected to red uce the toxicity and clastogenicity in clinical applications of etoposide o r quinolone antibiotics in dose-limiting normal tissues.