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提高肿瘤细胞的放射敏感性以提高放射治疗的效果,一直是临床放射治疗追求的目标之一。提高放射敏感性的策略,已从最初的提高细胞氧合水平,逐步发展到阻断放射引起的DNA双链断裂修复方向上。细胞主要通过同源重组修复和非同源末端连接修复的方式修复DNA双链断裂。阻断DNA双链断裂修复已成为提高放射敏感性的一个新的靶点和新的治疗策略。随着对放射导致的DNA双链断裂修复机制认识的深化,各种阻断修复的药物得到了开发并进入临床试验阶段。最近,组蛋白去乙酰酶(histone deacetylase,HDAC)阻滞剂因其细胞毒性小,且在正常细胞和肿瘤细胞之间的阻滞作用差别大,而成为广泛研究的药物,提示在未来的肿瘤治疗中具有重要作用。
组蛋白去乙酰酶阻滞剂的放射增敏作用
Enhancement of radiation response by histone deacetylase inhibitor
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摘要: 放射治疗是肿瘤的重要治疗手段之一,辐射可以导致细胞DNA双链断裂。细胞主要通过同源重组修复和非同源末端连接修复方式修复DNA双链断裂。随着对双链DNA损伤修复机制认识的深化,组蛋白去乙酰酶(HDAC)阻滞剂成为提高放射敏感性的一种新策略。HDAC可分为4类。HDAC阻滞剂可非特异性地或特异性地阻滞这4类HDAC,使组蛋白乙酰化水平提高,染色体解螺旋,核小体结构改变。一方面使DNA更易受到辐射的影响;另一方面通过降低E2F1转录因子活性抑制损伤修复蛋白Ku80、Rad51等的表达,使其不能募集DNA损伤修复蛋白,且不能形成相应的蛋白复合物,使同源重组修复和非同源末端连接修复作用延缓,在伴有或不伴有肿瘤细胞凋亡增加的情况下,提高放射敏感性。现已有一些临床试验在进行中,并取得了初步的结果。
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关键词:
- 辐射耐受性 /
- 组蛋白去乙酰酶阻滞剂
Abstract: Radiotherapy is an essential part of cancer treatment, which leads to DNA double strains break. Homogeneous recombination and heterogeneous end conjunction are the main ways which can repair DNA double strains break in the cells. It is a novel strategy, which as recognize as the mechanism of damage to DNA strains, that radiosensitivity is enhanced by histone deacetylase(HDAC)inhibitor. HDAC inhibitor is able to antagonize specifically or nonspecifically HDAC whom is forming as four various sorts, as a consequence enhancing level of histone deacetylase, decoilization of chromosome and alternation on molecular structure of nucleolus. Firstly DNA is simply influenced by radioactivity due to HDAC inhibitor, and then HDAC inhibitor effects on decline activity of E2F1 transcript factors, which cause directly expressional inhibition on the repair proteins including Ku80, Rad51, thus the molecules are unable to recruited and polymerized into correspond protein compound, as a result of HDAC inhibitor the function of homogeneous recombination and heterogeneous end conjunction becomes minimized. As the circumstances are shown involving augment or non-augment of apoptosis among cancer cells, HDAC inhibitor enhance the radiosensitivity eventually, which has been applicated into clinical trials and obtain primary achievement.-
Key words:
- Radiation tolerance /
- Histone deacetylase inhibitors
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