Murray D, Altschuler E M, Kerr M S, Vanankeren S C, Meyn R E, Milas L
Department of Experimental Radiotherapy, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Int J Radiat Biol. 1988 Aug;54(2):269-83. doi: 10.1080/09553008814551701.
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.
我们研究了氨硫醇WR - 255591及其硫代磷酸酯衍生物WR - 3689对通气培养的中国仓鼠卵巢细胞的辐射防护作用。在浓度高达10 mmol dm⁻³时，WR - 3689对γ辐射的致死效应几乎没有防护作用。另一方面，游离硫醇WR - 255591能有效保护这些细胞，在浓度为6 mmol dm⁻³时，细胞存活的保护因子（PF）为2.3。分别使用碱性（pH 12.1）和中性（pH 7.0或9.6）洗脱法测定了WR - 255591对γ射线诱导的DNA单链断裂（ssb）和双链断裂（dsb）的诱导及修复的影响。根据这些数据计算出的PF与细胞存活测定的PF进行了比较。WR - 255591（6 mmol dm⁻³）对DNA ssb和dsb的诱导均有防护作用；然而，ssb（PF为1.23）和dsb（在pH 7.0时PF为1.83，在pH 9.6时PF为1.70）的修饰程度均小于相同条件下（在冰上照射）测定的细胞存活的修饰程度（PF为2.3）。在照射前用WR - 255591处理细胞会延迟随后的ssb修复速率，但对dsb修复没有影响。照射后用该药物处理会轻微延迟ssb修复，但对细胞存活没有影响。观察到DNA链断裂的PF低于细胞存活的PF，这表明WR - 255591的辐射防护作用可能并非源于所有类型DNA损伤诱导的均匀减少。相反，该药物可能对DNA损伤亚类的诱导有差异地提供防护——这也可以解释其对ssb修复动力学的影响——和/或增强细胞恢复过程。
