WR-1065, the active metabolite of amifostine, mitigates radiation-induced delayed genomic instability.
Compounds that can protect cells from the effects of radiation are important for clinical use, in the event of an accidental or terrorist-generated radiation event, and for astronauts traveling in space. One of the major concerns regarding the use of radio-protective agents is that they may protect cells initially, but predispose surviving cells to increased genomic instability later. In this study we used WR-1065, the active metabolite of amifostine, to determine how protection from direct effects of high- and low-LET radiation exposure influences genomic stability. When added 30 min before irradiation and in high concentrations, WR-1065 protected cells from immediate radiation-induced effects as well as from delayed genomic instability. Lower, nontoxic concentrations of WR-1065 did not protect cells from death; however, it was effective in significantly decreasing delayed genomic instability in the progeny of irradiated cells. The observed increase in manganese superoxide dismutase protein levels and activity may provide an explanation for this effect. These results confirm that WR-1065 is protective against both low- and high-LET radiation-induced genomic instability in surviving cells.
Department of Radiation Oncology, Radiation Oncology Research Laboratory, University of Maryland School of Medicine, Baltimore, MD, USA.
Jaroslaw
J
Dziegielewski
Janet E
JE
Baulch
Wilfried
W
Goetz
Mitchell C
MC
Coleman
Douglas R
DR
Spitz
Jeffrey S
JS
Murley
David J
DJ
Grdina
William F
WF
Morgan
D004999:Amifostine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D015179:Colorectal Neoplasms / Q000473:pathology; D004307:Dose-Response Relationship, Radiation; D042822:Genomic Instability / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008624:Mercaptoethylamines / Q000494:pharmacology*; D015162:Micronucleus Tests; D011836:Radiation Tolerance; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014965:X-Rays; D000099156:Superoxide Dismutase 2
D004999:Amifostine; D049452:Green Fluorescent Proteins; D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane