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Further Evidence That the Radioprotective Aminothiol, WR-1065, Catalytically Inactivates Mammalian Topoisomerase II¹

DuPont Pharmaceuticals, Stine-Haskell Research Center, Newark, Delaware 19714-0030 [R. D. S.], and Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 60637 [D. J. G.]

It has recently been proposed that the thiol form of the cytoprotective drug amifostine that is designated WR-1065 [2-((aminopropyl)amino)ethanethiol] exerts its cytoprotective effects in part via a catalytic inhibition of DNA topoisomerase II (topo II) . This in turn leads to the subsequent accumulation of cells in G₂ phase and a prolongation of the cell cycle. We have used a Chinese hamster V79 cell-based micronucleus assay to further evaluate this hypothesis. It is demonstrated that WR-1065 strongly inhibits the clastogenesis of the topo II poisons etoposide and clinafloxacin at clinically attained exposure levels while having no effect on clastogenesis induced by topo II-noninteractive chemicals. These findings are consistent with the hypothesis that WR-1065 is a catalytic inhibitor of topo II in mammalian cells. These studies also suggest that WR-1065 might be expected to reduce the toxicity and clastogenicity in clinical applications of etoposide or quinolone antibiotics in dose-limiting normal tissues.

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