ROS-scavenger and radioprotective efficacy of the new PrC-210 aminothiol.
ROS-scavenger and radioprotective efficacy of the new PrC-210 aminothiol.
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DOI：
10.1667/rr2806.1
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发表时间：
2012-07
影响因子：
3.4
通讯作者：
Fahl WE
中科院分区：
文献类型：
--
作者：
Peebles DD;Soref CM;Copp RR;Thunberg AL;Fahl WE
为了寻找局部用药有效、全身用药副作用少的新型氨硫醇放射防护剂，设计并合成了一系列新的氨基硫醇放射防护剂。氨基硫醇设计中的三个关键元素是：(1)小尺寸，用于有效的跨膜扩散；(2)烷基主干上的正电胺，用于与DNA主干的强离子相互作用；以及(3)垂直的烷基侧链，其末端的硫醇从DNA主干伸出，使DNA周围的活性氧物种能够清除。我们采用了几种体外实验来鉴定原型氨硫醇PRC-210的有效性：对活性氧诱导的质粒DNA划痕的保护，检测氨硫醇-活性氧副产物的质谱法，鼠伤寒沙门氏菌的诱变，对人细胞生长的抑制，p21表达的蛋白质印迹，以及流式细胞仪分析。此外，还使用了两种体内试验来评估放射防护效果；建立了SpragueDawley大鼠背部皮肤放射性皮炎试验来筛选局部应用氨硫醇的效果，并对全身注射PRC-210和全身照射后ICR小鼠的存活进行了评分。PRC-210能有效清除活性氧，完全保护超螺旋DNA免受活性氧的损伤。PRC-210及其类似物PRC-211均不是细菌诱变剂。在细胞培养中，PRC-210应用于二倍体人成纤维细胞：(1)抑制细胞生长，IC70值为4.1 mM；(2)诱导p21表达水平；(3)洗脱含PRC-210的培养液后，细胞周期被逆转为G1/S期。在啮齿类动物中，PRC-210是一种有效的放射防护剂，表现为：(1)皮肤照射前局部使用(370 mM乙醇：丙二醇：水溶液)可完全预防2~3级放射性皮炎；(2)腹腔注射可完全预防2~3级放射性皮炎。皮肤照射前注射(2 0 0μg/g体重)，(3)全身照射剂量为10 0%致死剂量(8.75Gy)时，小鼠100%存活。照射前注射(2 5 2μg/g体重=0.5×最大耐受量)，剂量减少倍数为1.6，与氨磷汀相同。这些数据表明，PRC-210氨基硫醇作为人类暴露前的辐射防护剂是一种合理的药物开发候选者。
To identify new aminothiol radioprotectors that are active when applied topically and have fewer side effects when administered systemically, a new family of aminothiol radioprotectors was designed and synthesized. Three key elements in the aminothiol design were, (1) small size for efficient transmembrane diffusion, (2) positive charged amines in alkyl backbone for strong ionic interaction with DNA backbone, and (3) a perpendicular, alkyl side-chain with a terminal thiol that is projected away from the DNA backbone to enable reactive oxygen species scavenging around DNA. Several in vitro assays were used to characterize the prototype aminothiol, PrC-210, for efficacy: protection against reactive oxygen species-induced plasmid DNA nicking, mass spectrometry to detect aminothiol-reactive oxygen species by-products, S. typhimurium mutagenesis, human cell growth inhibition, Western blot for p21 expression, and FACS analysis. Additionally, two in vivo assays were used to assess radioprotective efficacy; a Sprague-Dawley rat dorsal skin radiodermatitis assay was developed to screen for aminothiol efficacy when topically applied, and ICR mouse survival was scored after systemic PrC-210 administration and whole-body radiation. PrC-210 efficiently scavenged reactive oxygen species and completely protected supercoiled plasmid DNA against reactive oxygen species-induced damage. Neither PrC-210 nor its analog PrC-211 were bacterial mutagens. In cell culture, PrC-210 application to diploid human fibroblasts showed: (1) inhibition of cell growth with an IC70 of 4.1 mM, (2) induced levels of p21 expression, and (3) a G1/S-cell cycle block that was reversed after washout of PrC-210-containing medium. In rodents, PrC-210 was an effective radioprotector showing: (1) complete prevention of Grade 2–3 radiodermatitis when applied topically (370 mM in ethanol:propylene glycol:water solution) prior to skin irradiation, (2) complete prevention of Grade 2–3 radioder-matitis when administered by i.p. injection (200 μg/g of body weight) before skin irradiation, (3) 100% survival of mice from an otherwise 100% lethal dose of whole-body radiation (8.75 Gy) when administered by i.p. injection (252 μg/g of body weight = 0.5 × maximum tolerated dose) before irradiation, and (4) a dose reduction factor of 1.6, the same as amifostine. These data suggest that the PrC-210 aminothiol is a plausible candidate for drug development as a human pre-exposure radioprotector.
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DOI：
10.1016/j.ijrobp.2011.11.038
发表时间：
2012-04-01
影响因子：
7
作者：
Soref, Cheryl M.;Hacker, Timothy A.;Fahl, William E.
通讯作者：
Fahl, William E.
影响因子：
2.7
作者：
Copp, Richard R.;Peebles, Daniel D.;Fahl, William E.
通讯作者：
Fahl, William E.
DOI：
10.1016/0360-3016(88)90387-2
发表时间：
1988-06-01
影响因子：
7
作者：
KLIGERMAN, MM;TURRISI, AT;RUBIN, P
通讯作者：
RUBIN, P
影响因子：
5.3
作者：
STEVENS, CW;BRONDYK, WH;FAHL, WE
通讯作者：
FAHL, WE
影响因子：
3.4
作者：
ZHENG, SX;NEWTON, GL;WARD, JF
通讯作者：
WARD, JF