细胞凋亡与辐射敏感性

随着细胞凋亡与放射治疗关系的深入研究,有必要搞清楚细胞凋亡与肿瘤细胞辐射敏感性的关系。为临床放疗提供新的预测及评估指标,近年来的研究表明,细胞凋亡与辐射敏感性存在着微妙而复杂的关系。本文着重讨论细胞凋亡的速率,周期时相及辐射剂量速率等方面与辐射敏感性的关系。     

p53状态与人类肿瘤细胞系放射敏感性的关系

ｐ５３状态与人类肿瘤细胞系放射敏感性的关系［英］／ＳｉｌｅｓＥ…∥ＢｒＪＣａｎｃｅｒ．－１９９６，７３（１）．－５８１～５８８用放射敏感性不同的８种人类肿瘤细胞系，观察辐射前后ｐ５３水平的变化和辐射诱导的细胞延迟、细胞凋亡与细胞的放射敏感性的关系。肿...     

亚致死剂量γ射线照射后小鼠脾脏CD95阳性淋巴细胞变化规律的研究

观察γ射线照射后小鼠脾脏淋巴细胞凋亡的变化规律与ＣＤ９５（Ｆａｓ）表达的关系。方法采用ＰＩ染色及双荧光流式细胞术研究不同剂量γ射线照射后不同时间，小鼠脾脏淋巴细胞凋亡及ＣＤ９５表达的规律。结果小鼠脾脏淋巴细胞对不同剂量照射的凋亡敏感性差异有显著性，４Ｇｙ照射后凋亡率最高（在２～６Ｇｙ之间观察），淋巴细胞表面Ｆａｓ的表达随照射后细胞凋亡率的变化而改变。结论脾脏淋巴细胞在辐射后表现出明显的Ｆａｓ介导的凋亡，Ｂ细胞较Ｔ细胞具有更高的辐射凋亡敏感性。     

辐射诱导凋亡与放疗的关系

从几方面综述辐射诱导凋亡：凋亡和有丝分裂相关死亡的定量比较；辐射诱导凋亡与放疗的关系；分次放疗期间凋亡敏感细胞中新细胞的补充；辐射诱导凋亡的调节；今后需要研究的辐射诱导凋亡问题     

肿瘤辐射敏感性与细胞凋亡

辐射敏感性是肿瘤细胞复杂的生物学现象,在辐射诱导的细胞反应中具有不同的组织细胞类型特异性。肿瘤瘤射敏感性与辐射诱导的细胞凋亡密切相关,并受P53及其相关蛋白、Bcl-2基因家族蛋白、Fas及神经鞘磷脂-神经酰胺介导的信号途径、caspases级联反应等调控。     

辐射敏感性影响因素研究

辐射敏感性受到许多因素的影响。以生殖细胞损伤、细胞遗传学损伤、细胞凋亡、DNA损伤和修复作为观察终点,结果显示辐射敏感性存在着年龄差别,遗传因素、性别、生活习惯(如吸烟)、小剂量照射等因素对辐射敏感性也存在不同程度的影响。     

DNA损伤修复与细胞凋亡

：细胞ＤＮＡ的损伤修复是影响细胞存活和死亡的主要原因，细胞缺乏修复能力，其辐射敏感性就会增加。近年来，ＤＮＡ损伤修复的机制已被逐步阐明。本文介绍ＤＮＡ损伤修复和细胞凋亡发生的机制及其与细胞周期、细胞增殖关系的研究进展。     

DNA损伤修复与细胞凋亡

细胞ＤＮＡ的损伤修复是影响细胞存活和死亡的主要原因，细胞缺乏修复能力，其辐射敏感性就会增加。近年来，ＤＮＡ损伤修复的机制已被逐步阐明。本文介绍了ＤＮＡ损伤修复和细胞凋亡发生和机制及其与细胞周期、细胞增殖关系的研究进展。     

反义STAT3寡核苷酸对B16细胞辐射敏感性的研究

目的 探讨反义STAT3转染鼠恶性黑色素瘤B16细胞后,肿瘤细胞辐射敏感性的变化。方法 利用反义寡核苷酸转染B16细胞后,以不同剂量γ射线照射。通过CCK-8试剂盒检测细胞增殖变化,Hoechst33258染色对细胞凋亡作形态学上的观察。用Annexin V/PI复染,流式细胞仪检测细胞早期凋亡率的变化。结果 反义STAT3转染后加以γ射线照射,B16细胞的增殖相比于两者单独作用组受到明显抑制,细胞凋亡水平也增加。结论 反义STAT3寡核苷酸联合γ射线对B16细胞的增殖抑制和诱导凋亡作用明显增强,提高了鼠黑色素瘤B16细胞的辐射敏感性;表明阻断STAT3蛋白表达可能成为一种新的提高肿瘤辐射敏感性的有效手段。     

个体辐射敏感性差异的研究进展及意义

个体对电离辐射损伤效应的敏感性具有很大的差异。早先发现的一些遗传性辐射敏感综合症中，其杂合子亦表现出较高的辐射敏感性和肿瘤易感性；通过对辐射敏感性不同的细胞系间的比较研究发现，某些特定基因改变与辐射敏感性相关。本文从ｐ５３基因突变、细胞凋亡和辐射诱导的遗传不稳定性等方面综述了个体辐射敏感性差异的机制及意义。     

Relationships between acute reactions to radiotherapy in head and neck cancer patients and parameters of radiation-induced DNA damage and repair in their lymphocytes

PURPOSE: To study the relationship between lymphocyte radiosensitivity measured in vitro and acute reactions to radiotherapy in patients with head and neck cancer. MATERIALS AND METHODS: Acute reactions were measured in 34 patients using the Dische scale. Lymphocyte radiosensitivity was measured using the alkaline comet assay, the micronucleus assay, the nuclear division index and morphological assessment of apoptosis. RESULTS: There was a weak, statistically significant correlation between in vitro radiosensitivity measured as the rate of DNA damage repair and the cumulative radiation dose exerting the maximum acute reaction scored (r = -0.366, p = 0.039, n = 34). Subgroup analyses showed that for patients with a low level of radiation-induced DNA damage there was a statistically significant relationship between lymphocyte radiosensitivity measured as inhibition of proliferation and acute toxicity (r = -0.621, p = 0.007, n = 18). For patients with a high level of residual DNA damage, there was a relationship between lymphocyte radiosensitivity measured using the micronucleus assay and acute toxicity (r = -0.597, p = 0.023, n = 14). CONCLUSIONS: Combining two measures of radiosensitivity improves the ability to correlate in vitro lymphocyte radiosensitivity and acute radiotherapy toxicity data.     

凋亡相关基因与食管鳞状细胞癌放射敏感性相关关系的研究

目的 探讨凋亡相关基因ｂｃｌ－２,ｃ－ｍｙｃ,ｐ５３与食管鳞癌放疗敏感性的关系。方法 采用免疫组化ＬＳＡＢ方法检测食管癌活检组织中ｂｃｌ－２,ｃ－ｍｙｃ,ｐ５３基因表达水平,病人接受放射治疗观察疗效,分析基因表达与放射敏感性的关系。结果 ｂｃｌ－２蛋白表达阳性者放射敏感性明显低于表达阴性者,ｐ５３蛋白表达阳性者略差于阴性者;ｃ－ｍｙｃ基因表达与放射敏感性无关。结论 ｂｃｌ－２,ｃ－ｍｙｃ,ｐ５３等凋亡相关基因表达产物的检测及综合分析有助于食管鳞癌放疗疗效的预测。     

Relationship between apoptotic activity and radiosensitivity in solid tumors: does apoptosis always bring good clinical results?

Apoptosis has recently been considered to be a predictor of tumor response or outcome following chemotherapy or radiotherapy. Although apoptosis clearly occurs in the very early stages following such treatments, it is unclear whether its frequency correlates with the likelihood of tumor cure following radiotherapy, especially in solid tumors, where the major mode of cell death is necrosis. This review discuses the relationship between apoptotic activity and radiosensitivity or tumor response from various points of view, including experimental systems and clinical conditions.     

鼻咽癌细胞系CNE-2Z放射敏感性的异质性及其机理探讨

目的　进一步证实人鼻咽癌细胞系CNE 2Z确实存在着放射敏感性的异质性 ,并探讨其有关机理。方法　观察人鼻咽癌细胞系CNE 2Z亚克隆株H5和S1的裸鼠移植瘤放射敏感性的不同 ;用流式细胞仪、荧光显微镜、Western blot检测H5和S1凋亡能力的不同及凋亡相关蛋白表达的差异 ;用3H掺入法说明DNA合成抑制率与放射敏感性的不同 ;用RT PCR观察相关癌基因 (fas、p5 3)的表达与放射敏感性的关系。结果　鼻咽癌细胞系CNE 2Z中确实存在放射敏感性的异质性 ,H5、S1两种细胞的凋亡率都随着照射后时间的延长而增加 ,但H5比S1高且差异有统计学意义 (P <0 0 5 )。两种细胞的DNA合成率于放射前无差别 ;照射后都较放射前受到抑制 (P <0 0 5 ) ,H5受抑制程度大 (P <0 0 5 )。H5与S1细胞fas、p5 3基因的表达差异无统计学意义 (P >0 0 5 )。结论　本实验再次证实了鼻咽癌细胞系CNE 2Z确实存在放射敏感性异质性 ,并证实了其异质性的机理与细胞受射线照射后引起凋亡的能力不同有关、与DNA合成的抑制率成正相关、与癌基因fas、p5 3的表达无关。     

调节肿瘤放射敏感性的miRNAs研究进展

miRNA是一类非编码的小RNA, 它主要利用碱基互补配对的方式与特异性靶基因信使RNA的3'-非翻译区结合, 通过降解靶RNA或抑制蛋白质的翻译合成, 从而实现对靶基因转录后水平的调控。放射治疗是治疗肿瘤的主要手段之一, 肿瘤的辐射生物效应对其放疗效果至关重要, 也是确定某肿瘤组织辐射敏感或辐射耐受的一个重要因素。研究证实, miRNAs通过影响DNA损伤修复、细胞周期检查点、凋亡、信号转导、肿瘤组织微环境等因素参与肿瘤放疗敏感性的调控, miRNAs为肿瘤放射治疗提供了新途径。     

肿瘤辐射增敏机制研究进展

辐射增敏作用机制非常复杂，迄今为止尚无明确的解释。其机制主要包括改变肿瘤微环境、清除自由基和电子、细胞周期同步化、抑制DNA损伤修复、促进细胞凋亡和生物还原作用。辐射增敏作用机制的研究在提高肿瘤放疗效果方面具有重要的理论指导意义。     

Radiosensitivity of tumor cells. Oncogenes and apoptosis.

The success of treatment of cancer patients by radiotherapy largely depends on tumor radiosensitivity. Several molecular factors that determine the sensitivity of tumor cells to ionizing radiation have been identified during the last couple of years. Some of these factors are known as oncogenes and tumor suppressor genes. This review focuses on the influence of some of these molecular factors on a major determinant of radiosensitivity: i.e. programmed cell death or apoptosis. The crucial molecular step in ionizing radiation-induced apoptosis is the release of mitochondrial cytochrome c into the cell's cytosol. The ways the tumor suppressor protein p53, as well as the oncogenes ras and raf, c-myc and Bcl-2 can influence this process at different stages are presented. As will be discussed, the result of activation of an oncoprotein on tumor radiosensitivity depends on its mechanism of action and on the presence of other (oncogenic) factors, since complex interactions among many molecular factors determine the delicate balance between cell proliferation and cell death. The ongoing identification and characterization of factors influencing apoptosis will eventually make it possible to predict tumor radiosensitivity and thereby improve cancer treatment.     

MicroRNAs与结直肠癌辐射敏感性的关系及作用机制

结直肠癌目前是世界第三大肿瘤,手术治疗后约50%的患者会复发和转移,目前美国国立综合癌症网络（NCCN）肿瘤学临床实践指南推荐常规接受适型外照射治疗。由于放疗将显著增加不良反应,如何最大程度减小辐射剂量,提高辐射敏感性至关重要。近年来人们不仅发现了microRNAs参与了结直肠癌的发病和演进,而且越来越多的证据表明,microRNAs在结直肠癌的辐射敏感性中发挥了重要的作用。辐射引起的DNA损伤反应包括ATM的激活,组蛋白修饰和染色质重塑,细胞周期停滞,损伤修复和凋亡等系列过程,microRNAs可以通过作用于任何一个环节调节DNA损伤修复过程,从而调控肿瘤的辐射敏感性。本综述重点阐述microRNAs影响DNA损伤修复的作用机制,并展望了microRNAs通过影响肿瘤辐射敏感性在临床上的应用。     

Smac与肿瘤放射治疗

放射治疗是肿瘤治疗的一个重要手段,肿瘤的辐射敏感性与凋亡蛋白抑制家族(IAPs)和促凋亡蛋白第二线粒体来源的Caspase激活因子(Smac)密切相关。IAPs能够通过结合Caspase-3、7、9抑制凋亡,IAPs的高表达是肿瘤细胞出现辐射抵抗的重要机制之一。当细胞接收到凋亡刺激信号后,Smac即从线粒体释放至胞质内与IAPs结合从而释放Caspase,发挥其促凋亡活性。以IAPs为靶点的治疗可能会为肿瘤细胞克服放射抵抗打开新的视角。临床前的体内体外研究证明,这种联合治疗值得更进一步的临床研究。使用IAPs拮抗剂联合放射治疗可能会为更有效的放射治疗肿瘤患者铺平道路。     

Lymphocyte telomere length correlates with in vitro radiosensitivity in breast cancer cases but is not predictive of acute normal tissue reactions to radiotherapy

PURPOSE: To examine the hypothesis that lymphocyte telomere length may be predictive of both breast cancer susceptibility and severity of acute reactions to radiotherapy. MATERIALS AND METHODS: Peripheral blood lymphocyte cultures from breast cancer patients (with normal or severe skin reactions to radiotherapy) and normal individuals were assessed for in vitro radiosensitivity as measured by apoptosis, cell cycle delay and cytotoxicity. Telomere lengths were determined by a flow cytometric fluorescence in situ hybridization assay (FLOW-FISH). RESULTS: Female breast cancer cases (n = 24) had reduced lymphocyte telomere lengths by comparison with healthy controls (n = 20, p < 0.04). However, the average age of healthy controls was less (45.4) than cases (53). When the control group was modified to give a better age match (51.5, n = 13) the reduced telomere length in cases was not significantly different from controls. Lymphocytes from breast cancer cases also showed reduced cell cycle delay (p < 0.001) and increased apoptosis (p < 0.01) following irradiation in vitro at 3 and 5 Gy respectively, compared to healthy controls. Statistical significance was maintained with the improved age matching of groups. Comparison of lymphocytes from breast cancer patients with normal (n = 11) and severe (n = 13) skin reactions to radiotherapy failed to identify differences in telomere length or cellular radiosensitivity in this limited sample. CONCLUSIONS: This study adds to the evidence suggesting a correlation between altered cellular radiosensitivity and breast cancer. However, in the cases investigated, telomere length does not appear to be predictive of acute skin reactions to radiotherapy.