Radioprotection of cultured Chinese hamster ovary cells by WR-255591.
We examined the radioprotective effect of the aminothiol WR-255591 and its phosphorothioate derivative WR-3689 on aerated cultured Chinese hamster ovary cells. At concentrations up to 10 mmol dm-3, WR-3689 afforded little protection from the lethal effects of gamma-radiation. The free thiol WR-255591, on the other hand, efficiently protected these cells, giving a protection factor (PF) for cell survival of 2.3 at a concentration of 6 mmol dm-3. The effects of WR-255591 on the induction and rejoining of gamma-ray-induced DNA single-strand breaks (ssb) and double-strand breaks (dsb) were measured using alkaline (pH 12.1) and neutral (pH 7.0 or 9.6) elution, respectively. PFs calculated from these data were compared with the PFs measured for cell survival. WR-255591 (6 mmol dm-3) protected against the induction of both DNA ssb and dsb; however, the magnitude of the modification of both ssb (PF of 1.23) and dsb (PF of 1.83 at pH 7.0 and 1.70 at pH 9.6) was less than that for cell survival (PF of 2.3) measured under identical conditions (irradiation on ice). Treatment of cells with WR-255591 prior to irradiation retarded the subsequent rate of ssb rejoining but had no effect on dsb rejoining. Postirradiation treatment with the drug slightly retarded ssb rejoining but had no effect on cell survival. The observation of lower PFs for DNA strand breaks than for cell survival suggests that radioprotection by WR-255591 probably does not result from a uniform decrease in the induction of all types of DNA lesions. Rather, the drug may differentially protect against the induction of subclasses of DNA damage--which could also explain the effects on the kinetics of ssb rejoining--and/or enhance cellular recovery processes.
D004999:Amifostine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D066298:In Vitro Techniques; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D011837:Radiation-Protective Agents; D013438:Sulfhydryl Compounds; C056753:S-2-(3-methylaminopropylamino)ethanethiol; C049344:S-2-(3-methylaminopropylamino)ethylphosphorothioic acid; D004999:Amifostine