title: Further evidence that the radioprotective aminothiol, WR-1065, catalytically inactivates mammalian topoisomerase II.
abstract: 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)alpha. 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.
authors.affiliation: DuPont Pharmaceuticals, Stine-Haskell Research Center, Newark, Delaware 19714-0030, USA. Ronald.D.Snyder@Dupontpharma.com
authors.forename: R D
authors.initials: RD
authors.lastname: Snyder
authors.forename: D J
authors.initials: DJ
authors.lastname: Grdina
mesh_terms: D000818:Animals; D002384:Catalysis; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D008624:Mercaptoethylamines / Q000494:pharmacology*; D015162:Micronucleus Tests; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
chemical_list: D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; D059005:Topoisomerase II Inhibitors; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane