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 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 acc...

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Bibliographic Details
Published inCancer research (Chicago, Ill.) Vol. 60; no. 5; pp. 1186 - 1188
Main Authors SNYDER, R. D, GRDINA, D. J
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 01.03.2000
Subjects
Animals
Biological and medical sciences
Catalysis
Cell Cycle - drug effects
Cell Line
Cricetinae
Drug toxicity and drugs side effects treatment
Medical sciences
Mercaptoethylamines - pharmacology
Micronucleus Tests
Pharmacology. Drug treatments
Radiation therapy and radiosensitizing agent
Radiation-Protective Agents - pharmacology
Topoisomerase II Inhibitors
Toxicity: urogenital system
Treatment with physical agents
Treatment. General aspects
Tumors
Antineoplastic agent
Radioprotector
Toxicity
Prevention
Isomerases
Mechanism of action
Quinolone derivatives
DNA topoisomerase (ATP-hydrolysing)
Micronucleus test
Enzyme
Rodentia
Etoposide
Enzyme inhibitor
Radiotherapy
Amifostine
In vitro
Podophyllotoxine derivatives
Vertebrata
Mammalia
Cytoprotector
Animal
Clinafloxacin
Aminothiol
Antibacterial agent
Hamster
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Summary: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.
ISSN:0008-5472
1538-7445