肿瘤放射敏感性影响因素的研究进展

目的:总结肿瘤放射敏感性影响因素与调节机制及其目前研究进展.方法:应用NCBI的PubMed和CHKD期刊全文数据库检索系统,以“放射敏感性、肿瘤和放疗”等为关键词,检索1999-01-2011-11相关文献1 209篇,纳入标准:1)放射敏感性相关因素;2)放射敏感性调节机制的研究;3)影响放射敏感性的药物、方法与增敏治疗.根据纳入标准符合分析的文献40篇.结果:肿瘤放射敏感性主要与肿瘤细胞固有的内在敏感性及肿瘤细胞微环境相关,目前已知与放射敏感性差异相关的因素包括细胞乏氧、细胞周期、DNA损伤修复和细胞凋亡等.与辐射生物效应过程相关的各种基因变异、基因多态性及袁观修饰,都可造成放射敏感性的差异.结论:研究肿瘤放射敏感性,对临床预测放疗疗效及肿瘤个体化治疗有重要意义.     

辐射诱导细胞凋亡在妇科肿瘤中的研究进展

 细胞凋亡是细胞在生理或病理因素的刺激下由基因调控的有序性自杀过程 ,放射治疗是妇科恶性肿瘤的主要治疗手段之一。探索辐射诱导凋亡的机制 ,凋亡与肿瘤细胞的辐射敏感性及抗性的关系 ,以及通过对凋亡的生物调节来改变肿瘤的放射敏感性是肿瘤放疗的关键。本文就此在妇科肿瘤中的相关研究作一综述。1　辐射诱导凋亡的异质性　　离体及在体实验均显示辐射可诱发多数肿瘤细胞凋亡 ,增加凋亡指数 (ａｐｏｐｔｏｓｉｓｉｎｄｅｘ ,ＡＩ) ,但有的即使给予较高射线剂量也不会发生凋亡。此外即便是同一类型肿瘤由于分化程度不同 ,辐射敏感性也可能不一样 ,这一现象称为凋亡的异质性。肿瘤细胞的凋亡异质性是我们运用放射治疗的理论依据。如何评估各肿瘤细胞的内在辐射敏感性一直是放射生物学家们研究的热点 ,但至今其机制尚不清楚 ,可能与细胞自发性凋亡本底水平 ,辐射时ＤＮＡ损伤程度及其修复动力学有关[1] 。2　辐射诱导凋亡的机制与辐射敏感性　　辐射诱导肿瘤细胞凋亡涉及众多的基因产物 ,可由不同的信号传导途径介导 ,并与细胞周期及细胞微环境密切相关。肿瘤辐射敏感性可能取决于细胞凋亡生化机制的恰当运行 ,而辐射抗性则与凋亡信号传导障碍 ,基因及其产物表达...     

EGFR抑制剂与肿瘤细胞放射敏感性

表皮生长因子受体(EGFR)在多种上皮来源的恶性肿瘤中存在过表达,其表达水平与肿瘤的放射敏感性呈负相关.大量研究表明,阻断EGFR表达的靶向抑制剂能够增加肿瘤细胞的放射敏感性,提高放射治疗的疗效,其机制可能与抑制细胞增殖、诱导细胞凋亡、干扰细胞周期分布、延长DNA的损伤修复有关.因此,运用EGFR抑制剂可以增强肿瘤细胞对放射的敏感性.     

Egr-1基因与肿瘤及放射治疗研究进展

目的:总结关于早期生长反应-1(Egr-1)基因在肿瘤和放射治疗中的研究进展.方法:应用PubMed及CNKI期刊全文数据库检索系统,以“Egr-1基因、肿瘤、放射治疗、细胞凋亡”为关键词,检索1993-01-2012-03的相关文献,共检索到英文文献691篇,中文文献129篇.纳入标准:1)Egr-1基因的结构;2)Egr-1基因在肿瘤中的表达;3)Egr-1基因对肿瘤的作用;4)Egr-1基因与放射治疗.根据纳入标准符合分析文献41篇.结果:Egr-1基因的表达存在于绝大多数的肿瘤中,对肿瘤的发生和发展具有抑制或促进作用;肿瘤细胞放射后可诱导Egr-1基因表达,并可引起下游基因表达及细胞凋亡;放射后的Egr-1基因表达水平与肿瘤细胞凋亡有关.结论:Egr-1基因在肿瘤中具有重要作用,对其不断深入研究可为肿瘤的治疗尤其是放疗提供更多新的依据.     

E2F转录因子与肿瘤基因治疗

E2F转录因子与细胞增殖、凋亡及癌变密切相关.各种与E2F转录因子相关的肿瘤基因治疗已在动物实验中取得良好效果.早期基因1A区的2保守区(E1A-CR2)缺失和携带E2F1启动子的增殖型腺病毒载体,可选择性在多种肿瘤细胞中增殖,其增殖能力甚至超过了野生腺病毒,是非常有潜力的肿瘤基因治疗手段.现对E2F转录因子在细胞周期调控、凋亡、肿瘤发生及相关肿瘤基因治疗等方面的研究作一综述.     

内质网应激调节顺铂引起的肿瘤细胞凋亡

目的:总结国内外关于内质网应激在化疗药物顺铂诱导肿瘤细胞死亡中的作用及研究进展.方法:应用Medline和CNKI期刊全文数据库系统,以"肿瘤抑制因子p53、DNA损伤应激反应、细胞凋亡、内质网应激"为关键词,检索2000-2010年的相关文献,共检索到英文文献1256篇和中文文献32篇.纳入标准:1)肿瘤抑制因子p53的调节及其引发的细胞凋亡分子机制;2)内质网应激的发生条件及内质网应激反应的分子调控;3)内质网应激在肿瘤细胞治疗中对凋亡的影响.根据纳入标准,符合分析的文献21篇.结果:内质网应激与肿瘤抑癌基因p53蛋白及其细胞凋亡作用有重要关系.传统的化疗药物对某些肿瘤细胞有耐药性,内质网应激相关调控可能会增加化疗药物对肿瘤细胞的杀伤作用.结论:抑制肿瘤细胞的内质网应激状态为肿瘤的治疗提供了一个新的思路.     

p21/WAF-1/CIP-1与宫颈癌放射敏感性的关系

已知凋亡受多种基因调控，其中p21／WAF-1／CIP-1是近年来研究较多的基因，又简称p21。它通过作用于周期蛋白．周期蛋白依赖性激酶(cyclin-CDK)复合物及增殖细胞核抗原(proliferating cell nuclear antigen，PCNA)引起肿瘤细胞生长抑制及调控细胞凋亡，从而影响肿瘤的放射敏感性。笔者搜集了30例宫颈癌病例，通过研究细胞凋亡与肿瘤放射敏感性以及p21与细胞凋亡的关系，探讨p21对宫颈癌放射敏感性的作用。     

HER-3基因表达对HER-2阳性型乳腺癌细胞放射敏感性的影响及作用机制

目的:探讨人表皮生长因子受体-3（human epidermal growth factor receptor-3,HER-3）表达对HER-2阳性型乳腺癌细胞放射敏感性的影响。方法:使用慢病毒颗粒感染HER-2阳性型乳腺癌细胞系（AU-565、SKBR-3）构建HER-3基因敲低细胞系模型,蛋白质印迹法（Western blot）及实时定量PCR(RT-qPCR)技术检测感染的效率。克隆形成实验测定不同组别乳腺癌细胞放射增敏效果。将HER-3敲低组与对照组细胞分别给予X线照射（6 Gy,6 MV,源皮距100 cm）,流式细胞术测定不同组别细胞凋亡率以及细胞周期分布的变化。免疫荧光法检测细胞辐射后不同时间段的γH2AX焦点数,评估辐射后DNA损伤情况,蛋白质印迹法检测细胞周期调控相关蛋白CyclinB1的表达。结果:克隆形成实验结果显示,HER-3敲低组乳腺癌细胞放射敏感性增强。流式细胞术结果显示,HER-3敲低后,HER-2阳性型乳腺癌细胞辐射后凋亡率明显增加,细胞周期G2期分布比例提高。免疫荧光结果显示,HER-3敲低后,HER-2阳性型乳腺癌细胞γH2AX焦点数目在辐射后先增加后降低,较对照组峰值更高,降低时趋势更慢,提示HER-3敲低可增强辐射诱导的DNA损伤,减少DNA修复。蛋白质印迹法结果显示,细胞周期相关驱动蛋白CyclinB1表达降低。结论:HER-3基因敲低后一方面增加了HER-2阳性型乳腺癌细胞辐射后DNA的损伤并减缓其修复能力,促进细胞凋亡;另一方面通过下调细胞周期蛋白CyclinB1的表达,增加G2期细胞分布,提升了放射敏感性。     

两株人肝癌细胞QSG-7701和HepG2放射敏感性的体外研究

在研究肿瘤的辐射效应之初就有人发现 [1], 各种肿瘤细胞对辐射的敏感性有明显差异 , 因而在接受放射治疗时效果也不一样 . 体外培养细胞株的存活分数 (surviving fractionm,SF)在受到 2 Gy照射后 (简称 SF2)可以在 0.01～ 0.90之间变动 , 即使是同一肿瘤的不同细胞株 , SF2也可以相差数十倍 [1]. 放射诱发细胞凋亡现象是近年放射生物学研究的一个热点 . 有人在研究鼠的肿瘤时发现 [2], 细胞放射反应与照射后凋亡水平具有相关性 .     

E2F-1与细胞凋亡

细胞周期的调控涉及到众多细胞因子的参与，细胞周期相关转录因子E2F家族是其重要的调控环节之一。其中E2F-1既可以调控细胞周期G1向S期的过渡，又可以诱导许多正常和肿瘤细胞的凋亡，兼有癌基因和抑癌基因的特性。尽管E2F-1通过pRb及相关蛋白等多种细胞周期依赖蛋白及激酶的相互作用调控细胞周期的通路比较明确，但是其诱导细胞凋亡的复杂机制还不甚明确，基于近期的研究对E2F-1诱导细胞凋亡的通路做以下综述。     

p53基因增加肿瘤放射治疗敏感性的机制

在肿瘤放疗过程中,p53基因的正常功能对肿瘤细胞的凋亡和提高放射敏感性起了关键性作用。野生型p53基因通过激活或抑制一系列基因,使肿瘤细胞周期阻滞,抑制肿瘤细胞放射损伤的修复,促进肿瘤细胞的凋亡,以及在乏氧环境中对促进肿瘤细胞凋亡至关重要,增强了肿瘤细胞对放疗的敏感性。     

Role of cell cycle in mediating sensitivity to radiotherapy

Multiple pathways are involved in maintaining the genetic integrity of a cell after its exposure to ionizing radiation. Although repair mechanisms such as homologous recombination and nonhomologous end-joining are important mammalian responses to double-strand DNA damage, cell cycle regulation is perhaps the most important determinant of ionizing radiation sensitivity. A common cellular response to DNA-damaging agents is the activation of cell cycle checkpoints. The DNA damage induced by ionizing radiation initiates signals that can ultimately activate either temporary checkpoints that permit time for genetic repair or irreversible growth arrest that results in cell death (necrosis or apoptosis). Such checkpoint activation constitutes an integrated response that involves sensor (RAD, BRCA, NBS1), transducer (ATM, CHK), and effector (p53, p21, CDK) genes. One of the key proteins in the checkpoint pathways is the tumor suppressor gene p53, which coordinates DNA repair with cell cycle progression and apoptosis. Specifically, in addition to other mediators of the checkpoint response (CHK kinases, p21), p53 mediates the two major DNA damage-dependent cellular checkpoints, one at the G(1)-S transition and the other at the G(2)-M transition, although the influence on the former process is more direct and significant. The cell cycle phase also determines a cell's relative radiosensitivity, with cells being most radiosensitive in the G(2)-M phase, less sensitive in the G(1) phase, and least sensitive during the latter part of the S phase. This understanding has, therefore, led to the realization that one way in which chemotherapy and fractionated radiotherapy may work better is by partial synchronization of cells in the most radiosensitive phase of the cell cycle. We describe how cell cycle and DNA damage checkpoint control relates to exposure to ionizing radiation.     

p53基因增加肿瘤放射治疗敏感性的机制

在肿瘤放疗过程中,p53基因的正常功能对肿瘤细胞的凋亡和提高放射敏感性起了关键性作用。野生型p53基因通过激活或抑制一系列基因,使肿瘤细胞周期阻滞,抑制肿瘤细胞放射损伤的修复,促进肿瘤细胞的凋亡,以及在乏氧环境中对促进肿瘤细胞凋亡至关重要,增强了肿瘤细胞对放疗的敏感性。     

DNA repair and tumour radiosensitivity: focus on ATM gene

Numerous parameters influenced tumour radiosensitivity. The number of clonogenic cells, growth fraction, hypoxia and intrinsic radiosensitivity are among the most important determinants of radiocurability. Detection of DNA damage and repair pathways are important components of intrinsic radiosensitivity. ATM plays a major role in the cellular response to ionizing radiation: it induced DNA repair, cell cycle arrest, and apoptosis via induction of p53. Analysis of single nucleotide polymorphisms could help us to predict normal tissue sensitivity on an individual basis. Mutations of ATM is probably involved in some cases of severe radiation-induced late effects. Measure of residual double-strand breaks by immunochemistry of H2AX, but also ATM or MRE11, is another way to evaluate tumour radiosensitivity. Integration of genomics and functional approach are needed to better predict what the best candidates for a curative radiotherapy are.     

The molecular and cellular basis of radiosensitivity: implications for understanding how normal tissues and tumors respond to therapeutic radiation

We have provided an overview of recent studies that have greatly expanded our knowledge of the molecular and cellular mechanisms that determine the sensitivity or resistance to ionizing radiation. Much of this knowledge was obtained by studying tumor and nontumor cell types that under- or overexpress proteins involved in the regulation of the DNA damage response, cell cycle progression, growth factor signal transduction, and apoptosis. These findings may ultimately be useful in devising new strategies to improve the therapeutic ratio in cancer treatment. Despite the rapid advances in knowledge of cellular functions that affect radiosensitivity, we still cannot account for most of the clinically observed heterogeneity of normal tissue and tumor responses to radiotherapy; nor can we accurately predict which individual tumors will be locally controlled and which patients will develop more severe normal tissue damage after radiotherapy. However, several candidate genes for which deletion or loss of function mutations may be associated with altered cellular radiosensitivity (e.g., ATM, p53, BRCA2) have been identified. Some of the differences in normal tissue sensitivity to radiation may occur because of mutations with milder effects, heterozygosity, or polymorphisms of these genes. Finally, molecular mechanisms linking genetic instability, radiosensitivity, and predisposition to cancer are being examined.     

Downregulation of TMPRSS4 Enhances Triple-Negative Breast Cancer Cell Radiosensitivity Through Cell Cycle and Cell Apoptosis Process Impairment

Background: Radioresistance remains a challenge for cancer radiotherapy. The present study aims to investigate the role of TMPRSS4 in triple negative breast cancer (TNBC) cell radiosensitivity. Materials and Methods: After transfection of MDA-MD-468 triple negative breast cancer cells line by using the lentivirus vector, the effect of TMPRSS4 down-regulation on TNBC radiosensitivity was evaluated by using cloning assay and CCK-8 assay. The CCK-8 assay was also used for performing cell proliferation analysis. Western blot was carried out to detect the expression of certain proteins related to cell cycle pathways (cyclin D1), cell apoptosis pathways (Bax, Bcl2, and Caspase3), DNA damage and DNA damage repair (TRF2, Ku80 , ˠH2AX) . The cell cycle and cell apoptosis were also investigated using flow cytometer analysis. Results: TMPRSS4 expression was down-regulated in MDA-MB-468 cells which enhanced MDA-MB-468 cells radiosensitivity. TMPRSS4 silencing also improved IR induced cell proliferation ability reduction and promoted cell arrested at G2/M phase mediated by 6 Gy IR associated with cyclin D1 expression inhibition. Moreover, TMPRSS4 inhibition enhanced TNBC apoptosis induced by 6 Gy IR following by over-expression of (Bax, Caspase3) and down-regulation of Bcl2 as the pro-apoptotic and anti-apoptotic proteins, respectively. Otherwise, TMPRSS4 down-regulation increases  DNA damage induced by 6 Gy IR and delays DNA damage repair respectively illustrated by downregulation of TRF2 and permanent increase of Ku80 and ˠH2AX expression at 1 h and 10 h post-IR. Conclusion: Down-regulation of TMPRSS4 increases triple negative breast cancer cell radiosensitivity and the use of TMPRSS4 inhibitor can be encouraged for improving radiotherapy effectiveness in TNBC radioresistant patients.     

Knocking Down Nucleolin Expression Enhances the Radiosensitivity of Non-Small Cell Lung Cancer by Influencing DNA-PKcs Activity

Nucleolin (C23) is an important anti-apoptotic protein that is ubiquitously expressed in exponentially growingeukaryotic cells. In order to understand the impact of C23 in radiation therapy, we attempted to investigate therelationship of C23 expression with the radiosensitivity of human non-small cell lung cancer (NSCLC) cells.We investigated the role of C23 in activating the catalytic subunit of DNA-dependent protein kinase (DNAPKcs),which is a critical protein for DNA double-strand breaks (DSBs) repair. As a result, we found that theexpression of C23 was negatively correlated with the radiosensitivity of NSCLC cell lines. In vitro clonogenicsurvival assays revealed that C23 knockdown increased the radiosensitivity of a human lung adenocarcinomacell line, potentially through the promotion of radiation-induced apoptosis and adjusting the cell cycle to a moreradiosensitive stage. Immunofluorescence data revealed an increasing quantity of γ-H2AX foci and decreasingradiation-induced DNA damage repair following knockdown of C23. To further clarify the mechanism of C23in DNA DSBs repair, we detected the expression of DNA-PKcs and C23 proteins in NSCLC cell lines. C23 mightparticipate in DNA DSBs repair for the reason that the expression of DNA-PKcs decreased at 30, 60, 120 and 360minutes after irradiation in C23 knockdown cells. Especially, the activity of DNA-PKcs phosphorylation sitesat the S2056 and T2609 was significantly suppressed. Therefore we concluded that C23 knockdown can inhibitDNA-PKcs phosphorylation activity at the S2056 and T2609 sites, thus reducing the radiation damage repairand increasing the radiosensitivity of NSCLC cells. Taken together, the inhibition of C23 expression was shownto increase the radiosensitivity of NSCLC cells, as implied by the relevance to the notably decreased DNA-PKcsphosphorylation activity at the S2056 and T2609 clusters. Further research on targeted C23 treatment maypromote effectiveness of radiotherapy and provide new targets for NSCLC patients.