Gimeracil sensitizes cells to radiation via inhibition of homologous recombination
Gimeracil sensitizes cells to radiation via inhibition of homologous recombination
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DOI：
10.1016/j.radonc.2010.05.020
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发表时间：
2010-08-01
影响因子：
5.7
通讯作者：
Fukushima, Masakazu
中科院分区：
文献类型：
--
作者：
Takagi, Masaru;Sakata, Koh-ichi;Fukushima, Masakazu
背景和目的。5-氯-2,4-二羟基吡啶（Gimeracil）是一种口服氟嘧啶衍生物S-1的组成部分，最初在S-1中添加Gimeracil是为了抑制降解5-FU的二氢嘧啶脱氢酶，从而延长肿瘤组织中5-FU的浓度。我们利用多种缺乏非同源末端连接（NHEJ）或同源重组（HR）的细胞系，以及DLD-1和HeLa进行克隆实验，采用SCneo法研究了Gimeracil对DNA双链突变（DSB）修复机制的影响。结果γ - h2ax聚焦实验结果表明，Gimeracil对DNA双链突变（DSB）修复有抑制作用，但不增敏在SCneo实验中，Gimeracil降低了新阳性克隆的频率，并且对s期细胞的致敏作用大于G0/ g1。结论Gimeracil抑制HR。由于HR在放疗引起的DSBH修复中起关键作用，Gimeracil可能通过抑制HR介导的DNA修复途径来增强放疗的疗效(C) 2010 Elsevier Ireland Ltd。放射与肿瘤学96(2010)259-266版权所有
Background and purpose. 5-Chloro-2,4-dihydroxypyridine (Gimeracil) is a component of an oral fluoro-pyrimidine derivative S-1 Gimeracil is originally added to S-1 to yield prolonged 5-FU concentrations in tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We found that Gimeracil by itself had the radiosensitizing effectMethods and materials We used various cell lines deficient in non-homologous end-joining (NHEJ) or homologous recombination (HR) as well as DLD-1 and HeLa in clonogenic assay gamma-H2AX focus formation and SCneo assay was performed to examine the effects of Gimeracil on DNA double strand bleak (DSB) repair mechanismsResults Results of gamma-H2AX focus assay indicated that Gimeracil inhibited DNA DSB repair It did not sensitize cells deficient in HR but sensitized those deficient in NHEJ In SCneo assay, Gimeracil reduced the frequency of neo-positive clones Additionally, it sensitized the cells in S-phase more than in G0/G1Conclusions Gimeracil inhibits HR. Because HR plays key roles in the repair of DSBH caused by radiotherapy, Gimeracil may enhance the efficacy of radiotherapy through the suppression of HR-mediated DNA repair pathways (C) 2010 Elsevier Ireland Ltd. All rights reserved Radiotherapy and Oncology 96 (2010) 259-266