Protection against radiation-induced mutagenesis at the hprt locus by spermine and N,N"-(dithiodi-2,1-ethanediyl)bis-1,3-propanediamine (WR-33278).
Protection against radiation-induced mutagenesis at the hprt locus by spermine and N,N"-(dithiodi-2,1-ethanediyl)bis-1,3-propanediamine (WR-33278).
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通过精胺和 N,N"-(二硫二-2,1-乙二基)双-1,3-丙二胺 (WR-33278) 防止 hprt 位点发生辐射诱导突变。
DOI：
10.1093/mutage/9.4.355
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发表时间：
1994
期刊：
影响因子：
2.7
通讯作者：
Grdina,DJ
中科院分区：
文献类型：
--
作者：
Shigematsu,N;Schwartz,JL;Grdina,DJ
多胺精胺和二硫化物N，N″-（二硫代二-2，1-乙二基）双-1，3-丙二胺（WR-33278）是结构相似的能够与DNA结合的试剂。WR-33278是临床研究的放射防护剂S-2-（3-氨基丙基氨基）乙基硫代磷酸（WR-2721）的二硫化物部分。由于它们报道的结构和功能相似性，比较它们对中国仓鼠AA 8细胞中次黄嘌呤-鸟嘌呤磷酸核糖转移酶（hprt）位点的细胞存活和突变诱导的影响是有意义的。将WR-33278和精胺（浓度为0.01和0.001 mM）电穿孔到细胞中。在细胞暴露于750 cGy电离辐射之前30分钟或之后3小时进行电穿孔，300 V和125 μF。单独的电穿孔使细胞存活率降低到75%，但对hprt突变频率没有影响。浓度大于0.01 mM的精胺或WR-33278的电穿孔具有极强的毒性。细胞暴露于电穿孔和辐射引起增强的细胞杀伤和突变诱导，与辐射的顺序，随后3小时后电穿孔是毒性更大的协议。细胞存活率仅在照射前30分钟电穿孔0.01 mM精胺和WR-33278后增强。在所有试验条件下，观察到精胺和WR-33278对辐射诱导hprt突变的保护作用。精胺在暴露浓度为0.01和0.001毫米前30分钟或3小时后，照射减少突变频率的因素分别为2.2，1.2，1.9和2.2。WR-33278浓度为0.01和0.001 mM，在750 cGy照射后30分钟或3小时给药，分别使突变频率降低1.8、1.3、1.4和2.0倍。这些数据表明，硫代磷酸酯（WR-2721）和相关的氨基硫醇（WR-1065）和二硫化物（WR-33278）代谢物表现出的辐射保护和化学预防特性可能部分通过内源性精胺样多胺过程（即染色质稳定化）介导。这种机制将具有重要的意义，设计和开发新一代的药物用于辐射防护和化学预防。
The polyamine spermine and the disulfideN,N″-(dithiodi-2,1-ethanediyl)bis-1,3-propanediamine (WR-33278) are structurally similar agents capable of binding to DNA. WR-33278 is the disulfide moiety of the clinically studied radioprotective agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). Because of their reported structural and functional similarities, it was of interest to compare their effects on cell survival and mutation induction at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in Chinese hamster AA8 cells. WR-33278 and spermine (at concentrations of 0.01 and 0.001 mM) were electroporated into cells. Electroporation, 300 V and 125 μF, was performed either 30 min prior to or 3 h following exposure of cells to 750 cGy of ionizing radiation. Electroporation alone reduced cell survival to 75% but had no effect onhprtmutation frequency. The electroporation of either spermine or WR-33278 at concentrations greater than 0.01 mM was extremely toxic. The exposure of cells to both electroporation and irradiation gave rise to enhanced cell killing and mutation induction, with the sequence of irradiation followed 3 h later by electroporation being the more toxic protocol. Cell survival was only enhanced following electroporation of 0.01 mM of spermine and WR-33278 30 min prior to irradiation. Protection against radiation-inducedhprtmutations was observed for both spermine and WR-33278 under all experimental conditions tested. Spermine at exposure concentrations of 0.01 and 0.001 mM administered 30 min before or 3 h after irradiation reduced mutation frequencies by factors of 2.2, 1.2, 1.9 and 2.2, respectively. WR-33278 at concentrations of 0.01 and 0.001 mM administered 30 min or 3 h after irradiation with 750 cGy lowered mutation frequencies by factors of 1.8, 1.3, 1.4 and 2.0, respectively. These data suggest that the properties of radioprotection and chemoprevention exhibited by the phosphorothioate (WR-2721) and associated aminothiol (WR-1065) and disulfide (WR-33278) metabolites may be mediated in part via endogenous sperminelike polyamine processes (i.e. chromatin stabilization). Such a mechanism would have important implications with respect to the design and development of new generation drugs for use in radioprotection and chemoprevention.