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首页> 外文学位 >Altering DNA base excision repair: Use of nuclear and mitochondrial targeted N-methylpurine DNA glycosylase (MPG) to sensitize astroglia to chemotherapeutic agents.
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Altering DNA base excision repair: Use of nuclear and mitochondrial targeted N-methylpurine DNA glycosylase (MPG) to sensitize astroglia to chemotherapeutic agents.

机译：改变DNA碱基切除修复：使用核和线粒体靶向的N-甲基嘌呤DNA糖基化酶（MPG）使星形胶质细胞对化疗药物敏感。

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摘要

Mitochondrial DNA (mtDNA) is a sensitive target of anti-cancer DNA alkylating agents, and previous studies have revealed a strong correlation between cell type-specific mtDNA repair capacity and cell type-specific resistance in the central nervous system (CNS) to oxidation and alkylation treatment. An assessment of two primary cell types indicated that sensitivity in the CNS to DNA damaging agents may be attributable to an imbalance in mitochondrial base excision repair (BER). This study utilized a primary astrocyte model to investigate mtDNA repair modulation as a potential tool for sensitizing astrocytic tumors to genotoxic anti-cancer agents. An adenoviral-based expression system was employed to target high levels of N-methylpurine DNA glycosylase (MPG) to either the mitochondria or nucleus of primary astrocytes to test the hypothesis that an imbalance in mitochondrial BER would result in increased alkylation sensitivity in astrocytes. These studies revealed that increasing MPG activity dramatically increased BER kinetics in the mitochondria and nucleus. Modulating MPG activity in the mitochondria appeared to have little effect on alkylation sensitivity in primary astrocytes. However, increased nuclear MPG activity was lethal in astrocytes treated with methylnitrosourea (MNU). Caspase-3 cleavage was not detected in these transduced astrocytes, and both TUNEL and Annexin-V assays indicated that these alkylation sensitive astrocytes do not undergo a typical programmed cell death in response to MNU. An assessment of the steady-state levels of key apoptotic proteins suggests that the apoptotic machinery of astrocytes is adapted more for cell survival, thus astrocytes are less vulnerable to pro-apoptotic stimuli compared to other CNS cell types exhibiting greater sensitivity to chemotherapeutic agents. However, targeting this MPG-mediated alkylation sensitivity to astrocytic cells in combination with alkylating drugs and radiation might be a useful strategy for improving the prognosis for patients with astrocytoma.
机译：线粒体DNA（mtDNA）是抗癌DNA烷基化剂的敏感靶标，以前的研究表明，中枢神经系统（CNS）的细胞类型特异性mtDNA修复能力与细胞类型特异性抗性之间存在很强的相关性。烷基化处理。对两种原代细胞类型的评估表明，中枢神经系统对DNA损伤剂的敏感性可能归因于线粒体碱基切除修复（BER）的失衡。这项研究利用主要的星形胶质细胞模型来研究mtDNA修复调节作用，将其作为使星形细胞肿瘤对遗传毒性抗癌药敏感的潜在工具。基于腺病毒的表达系统被用于将高水平的N-甲基嘌呤DNA糖基化酶（MPG）靶向原代星形胶质细胞的线粒体或细胞核，以检验线粒体BER失衡会导致星形胶质细胞烷基化敏感性增加的假设。这些研究表明，增加MPG活性可大大增加线粒体和细胞核的BER动力学。调节线粒体中MPG活性似乎对原代星形胶质细胞的烷基化敏感性影响很小。但是，增加的核MPG活性在用甲基亚硝基脲（MNU）处理的星形胶质细胞中是致命的。在这些转导的星形胶质细胞中未检测到Caspase-3裂解，TUNEL和Annexin-V分析均表明，这些对烷基化敏感的星形胶质细胞并未响应MNU而经历典型的程序性细胞死亡。对关键细胞凋亡蛋白稳态水平的评估表明，星形胶质细胞的凋亡机制更适合细胞存活，因此，与其他对化学治疗剂表现出更高敏感性的中枢神经系统细胞相比，星形胶质细胞更不容易受到促凋亡的刺激。但是，将这种MPG介导的烷基化敏感性与烷基化药物和放射治疗相结合对星形细胞可能是改善星形细胞瘤患者预后的有用策略。

著录项

  • 作者

    Harrison, Jason F.;

  • 作者单位

    University of South Alabama.;

  • 授予单位 University of South Alabama.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 135 p.
  • 总页数 135
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;
  • 关键词

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