电离辐射与细胞动力学

细胞对电离辐射的反应取决于ＤＮＡ的损伤程度及细胞对此损伤的修复能力，损伤后修复能力和损伤质因细胞周期而异。因此，细胞动力学改变是影响治疗效果的重要因素。     

肿瘤放射治疗的加热增益

加温与放射相结合,常表现有协同作用,既加温可增强放射作用,这种协同作用有其特殊的生物学因素:1.提高温度增加了细胞的放射敏感性并降低了细胞亚致死损伤的修复能力,还增加了放射致死的可能性。     

临床放射生物学发展的前景和问题

最近一,二十年,在放射医学和放射生物学中产生了一个新的学科分支,即临床放射生物学或医学放射生物学,而且它已有了相当大的发展。这个学科的主要任务是利用在各个系统和不同生物结构水平进行放射生物学大量研究中获得的基本规律,分析人和动物的正常组织和肿瘤组织的放射损伤,作出科学论证,并在这个基础上制定和完善恶性肿瘤的放射治疗方法。苏联医学科学院放射医学研究所在这个领域里进行了积极的研究。本文拟对以往进行的研究工作,结合临床放射生物学的现代概念和发展前景,作一简要总结。苏联医学科学院放射医学研究所在放射医学、生物学和遗传学方面的大量研究工作为临床放射生物学的研究奠定了基础。研究得特别多的是:细胞放射损伤和恢复的机理,受照射细胞的细胞遗传效应的发生和修复的规律,以及各种能改变辐射敏感性的方法的效果。本研究所在阐明哺乳动物细胞放射损伤和脱氧     

NADH对正常肝细胞株LO2辐射后p53和bax表达的影响

放射治疗在于最大程度地杀伤肿瘤细胞和尽可能地减小正常组织细胞的损伤.但临床上往往对正常组织造成损伤,从而限制了肿瘤的放射治疗剂量的提高,特别是对于亚临床病灶的放射治疗.为此,减小正常组织细胞的放射损伤成为放射生物学研究的重要领域.本研究通过还原型辅酶NADH对辐射诱导的细胞凋亡及其凋亡信号传递分子p53、bax表达的影响,探讨NADH抗辐射诱导的细胞凋亡作用及其作用机理.     

NADH对正常肝细胞株L02辐射后p53和bax表达的影响

放射治疗在于最大程度地杀伤肿瘤细胞和尽可能地减小正常组织细胞的损伤。但临床上往往对正常组织造成损伤，从而限制了肿瘤的放射治疗剂量的提高，特别是对于亚临床病灶的放射治疗。为此，减小正常组织细胞的放射损伤成为放射生物学研究的重要领域。本研究通过还原型辅酶NADH对辐射诱导的细胞凋亡及其凋亡信号传递分子p53、bax表达的影响，探讨NADH抗辐射诱导的细胞凋亡作用及其作用机理。     

代谢重编程在电离辐射及其旁效应中的研究进展

代谢重编程是指肿瘤细胞为满足自身生长和能量的需求, 通过改变代谢模式来调节细胞生物学功能, 帮助自身抵御外界胁迫, 从而使细胞适应低氧、酸性、营养物质缺乏等微环境而快速增殖的现象。放射生物学研究发现, 电离辐射可通过诱导细胞代谢重编程产生辐射抗性;也可通过旁效应促进未受照射细胞发生代谢重编程, 从而赋予细胞癌变和辐射抗性能力。因此, 探索电离辐射和电离辐射旁效应中代谢重编程机制, 可以为辐射防护、放射治疗、放射损伤诊断等提供新的思路和理论依据。本文对代谢重编程在电离辐射及其旁效应中的研究进展进行综述。     

快速多分次放射治疗:178例晚期头颈鳞状细胞癌的临床结果

影响肿瘤的和正常组织的放射耐受性之主要生物学因素,业已证实为放疗期间的亚致死损伤和潜在致死损伤的修复、残存细胞的再增殖、细胞周期的再募集和再分配。作者于1976.1～1981.12对不能切除的晚期(Ⅲ、Ⅳ期)头颈鳞状细胞癌178例,采用小剂量多分次的快速放射治疗方案(超分次法)。第一组91例,按下面程序进行:第一周5天,每天照射8次,每次0.9Gy,每次间歇2小时,共     

人类放射生物学的最新进展

目前,在人类放射生物学领域中,放射治疗和辐射防护都发生着重大的变化。放射治疗 Kallman拓宽了与放射治疗有关组织和细胞放射生物学的看法。他提议,在受照组织经典细胞反应的五     

组蛋白去乙酰酶阻滞剂的放射增敏作用

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。     

放射抗性肺癌D6-R细胞亚系的特征分析

目的研究新的放射抗性肺癌D6-R细胞亚系在增殖活性、放射诱导的凋亡、DNA损伤与修复方面的特征，初步探讨D6-R细胞放射抗性的机理。方法以D6-R和D6细胞为实验对象，MTT法测定细胞生长曲线，流式细胞仪和荧光显微镜分析细胞凋亡状况，碱性单细胞凝胶电泳检测DNA单链断裂与修复。结果D6-R和D6细胞具有相同的增殖活性；照射前后均无明显的细胞凋亡发生；照射后D6-R、D6细胞的初始DNA单链断裂与修复能力存在统计学意义，放射抗性的D6-R细胞初始DNA单链断裂程度较轻，修复速率较快，修复后残存单链断裂较少。结论初始DNA损伤程度较轻，修复能力较强可能是D6-R细胞放射抗性的重要原因。     

环状RNA在DNA损伤修复中作用的研究进展

环状RNA （CircRNA）是一类由外显子、内含子或基因间区经反向剪接形成的非编码RNA,具有种类丰富、序列保守、结构稳定和细胞组织特异性等特点。CircRNA在多种恶性肿瘤中处于失调状态,其可通过调节放化疗后细胞DNA双链断裂的损伤修复功能,使肿瘤细胞发生增殖失控、远处转移和凋亡受阻等一系列不良反应,进而影响治疗效...     

Hyperthermic radiosensitization: mode of action and clinical relevance

PURPOSE: To provide an update on the recent knowledge about the molecular mechanisms of thermal radiosensitization and its possible relevance to thermoradiotherapy. SUMMARY: Hyperthermia is probably the most potent cellular radiosensitizer known to date. Heat interacts with radiation and potentiates the cellular action of radiation by interfering with the cells' capability to deal with radiation-induced DNA damage. For ionizing irradiation, heat inhibits the repair of all types of DNA damage. Genetic and biochemical data suggest that the main pathways for DNA double-strand break (DSB) rejoining, non-homologous end-joining and homologous recombination, are not the likely primary targets for heat-induced radiosensitization. Rather, heat is suggested to affect primarily the religation step of base excision repair. Subsequently additional DSB arise during the DNA repair process in irradiated and heated cells and these additional DSB are all repaired with slow kinetics, the repair of which is highly error prone. Both mis- and non-rejoined DSB lead to an elevated number of lethal chromosome aberrations, finally causing additional cell killing. Heat-induced inhibition of DNA repair is considered not to result from altered signalling or enzyme inactivation but rather from alterations in higher-order chromatin structure. Although, the detailed mechanisms are not yet known, a substantial body of indirect and correlative data suggests that heat-induced protein aggregation at the level of attachment of looped DNA to the nuclear matrix impairs the accessibility of the damaged DNA for the repair machinery or impairs the processivity of the repair machinery itself. CONCLUSION: Since recent phase III clinical trials have shown significant benefit of adding hyperthermia to radiotherapy regimens for a number of malignancies, it will become more important again to determine the molecular effects underlying this success. Such information could eventually also improve treatment quality in terms of patient selection, improved sequencing of the heat and radiation treatments, the number of heat treatments, and multimodality treatments (i.e. thermochemoradiotherapy).     

辐射损伤与修复的研究近况

肿瘤分子放射生物学的研究证实,通过诱导细胞凋亡途径可提高肿瘤细胞辐射敏感性,而且通过激活与细胞损伤和修复有关的靶分子、调整细胞微环境和调控细胞周期,可减小正常组织的损伤。     

Radiation-induced EGFR-signaling and control of DNA-damage repair

Purpose: Over the last decade evidence has accumulated indicating that cell membrane-bound growth factor receptor of the erbB family and especially the epidermal growth factor receptor EGFR (erbB1) mediates resistance of tumor cells to both chemo- and radiotherapy when mutated or overexpressed. More recently a novel link between EGFR signaling pathways and DNA repair mechanisms, especially non-homologous end joining (NHEJ) repair could be demonstrated. The following review summarizes the current knowledge on the role of EGFR and its downstream signaling pathways in the regulation of cellular radiation response and DNA repair.

Conclusion: The novel findings on radiation-induced EGFR-signaling and its involvement in regulating DNA-double strand break repair need further investigations of the detailed mechanisms involved. The results to be obtained may not only improve our knowledge on basic mechanisms of radiation sensitivity/resistance but also will promote translational approaches to test new strategies for clinically applicable molecular targeting.     

High levels of chromosome aberrations correlate with impaired in vitro radiation-induced apoptosis and DNA repair in human B-chronic lymphocytic leukaemia cells

Purpose : To investigate the relationship between the susceptibility of B-chronic lymphoid leukaemia (B-CLL) cells to DNA damage-induced apoptosis, the kinetics of DNA strand-break rejoining, and chromosome damage after exposure to ionizing irradiation. Materials and methods : Lymphocytes from B-CLL patients were γ-irradiated in vitro with 0.2-5 Gy and stimulated by Staphylococcus aureus cowan I (SAC I) for estimation of chromosomal damage. Induction of apoptosis after irradiation was studied in 50 patients by two methods: morphological characterization of apoptotic cells after fluorescent staining (Hoechst), and specific quantification of mono- and oligonucleosomes in cytoplasmic cell fractions (ELISA assay). Morphological chromosome damage was scored in the first cell generation after irradiation (13 patients). In parallel, the kinetics of DNA single-strand break rejoining were investigated by the alkaline comet assay (12 patients). Results : Ionizing irradiation did not induce apoptosis in lymphocytes from a subset of B-CLL patients. The results suggest that B-CLL cells resistant to radiation-induced apoptosis could repair DNA strand-breaks more rapidly and showed a higher level of chromosome aberrations than radiation-sensitive B-CLL cells. Conclusion : Each of three biological effects observed (apoptosis, kinetics of DNA single-strand-break repair, chromosomal damage) might be explained by different modifications occurring in irradiated B-CLL cells. Their convergence strongly suggests that resistance to apoptotic death initiation by DNA damage may be impeded by a rapid engaging of the DNA repair mechanisms. The higher level of chromosome aberrations observed in these cells suggests that the type of DNA repair system involved may generate inaccurate repair.     

Regulation of DNA repair kinetics in proliferative and quiescent tumor cells

The radiosensitivity and kinetics of repair of radiation-induced DNA damage were determined for proliferative (P) and quiescent (Q) cells of the mouse mammary adenocarcinoma line 67. 67 Q cells are more radiosensitive than 67 P cells. Radiation induced the same amount of DNA damage in both 67 P and 67 Q cells. Both 67 P and 67 Q cells repaired their DNA damage with biphasic kinetics, but the half-times for the fast and slow phase were longer in 67 Q cells. Q cell DNA appeared to be in a more compact or condensed chromatin structure and was less accessible to enzymatic digestion than P cell DNA. These data suggest that 67 Q cells are more sensitive to ionizing radiation than 67 P cells because they repair their radiation-induced DNA damage more slowly, perhaps as a result of their more condensed chromatin structure.     

High levels of chromosome aberrations correlate with impaired in vitro radiation-induced apoptosis and DNA repair in human B-chronic lymphocytic leukaemia cells

PURPOSE: To investigate the relationship between the susceptibility of B-chronic lymphoid leukaemia (B-CLL) cells to DNA damage-induced apoptosis, the kinetics of DNA strand-break rejoining, and chromosome damage after exposure to ionizing irradiation. MATERIALS AND METHODS: Lymphocytes from B-CLL patients were gamma-irradiated in vitro with 0.2-5 Gy and stimulated by Staphylococcus aureus cowan I (SAC I) for estimation of chromosomal damage. Induction of apoptosis after irradiation was studied in 50 patients by two methods: morphological characterization of apoptotic cells after fluorescent staining (Hoechst), and specific quantification of mono- and oligonucleosomes in cytoplasmic cell fractions (ELISA assay). Morphological chromosome damage was scored in the first cell generation after irradiation (13 patients). In parallel, the kinetics of DNA single-strand break rejoining were investigated by the alkaline comet assay (12 patients). RESULTS: Ionizing irradiation did not induce apoptosis in lymphocytes from a subset of B-CLL patients. The results suggest that B-CLL cells resistant to radiation-induced apoptosis could repair DNA strand-breaks more rapidly and showed a higher level of chromosome aberrations than radiation-sensitive B-CLL cells. CONCLUSION: Each of three biological effects observed (apoptosis, kinetics of DNA single-strand-break repair, chromosomal damage) might be explained by different modifications occurring in irradiated B-CLL cells. Their convergence strongly suggests that resistance to apoptotic death initiation by DNA damage may be impeded by a rapid engaging of the DNA repair mechanisms. The higher level of chromosome aberrations observed in these cells suggests that the type of DNA repair system involved may generate inaccurate repair.     

Differences in repair of radiation induced damage in two human tumor cell lines as measured by cell survival and alkaline DNA unwinding

We studied the relationship between the repair of radiation induced DNA strand breaks and cellular repair kinetics in two human tumor cell lines, NB-100 (neuroblastoma) and HN-1 (squamous cell carcinoma). Damage was quantified using the fluorometric analysis of DNA unwiding (FADU) for DNA damage, and cell survival was assessed using a clonogenic assay. In plateau phase cells repair of sublethal damage was virtually absent in NB-100 after 4 Gy (recovery ratio 1.0), whereas HN-1 cells did show sublethal damage repair (recovery ratio 1.4). Repair of potentially lethal damage was more pronounced in NB-100 cells (recovery ratio 2.3) than in HN-1 cells (recovery ratio 1.7) after 4 Gy. Graded doses of X-rays induced comparable levels of DNA damage in both tumor cell lines. However, in HN-1 cells more DNA strand breaks were repaired after 4 Gy, leaving about 25% of the initial damage unrepaired, whereas in NB-100 about 50% was unrepaired. This higher fraction of unrepaired DNA damage correlated well with the degree of sublethal damage repair which was lower in NB-100 than in HN-1 cell, but it did not correlate with the repair of potentially lethal damage, which was higher in NB-100 than in HN-1. Since the level of damage remaining post-irradiation may be the critical variable for survival, the FADU technique can contribute in elucidating the relationship between radiosensitivity and DNA damage repair capacity.     

Dotting the eyes: mouse strain dependency of the lens epithelium to low dose radiation-induced DNA damage

Purpose: Epidemiological evidence regarding the radiosensitivity of the lens of the eye and radiation cataract development has led to changes in the EU Basic Safety Standards for protection of the lens against ionizing radiation. However, mechanistic details of lens radiation response pathways and their significance for cataractogenesis remain unclear. Radiation-induced DNA damage and the potential impairment of repair pathways within the lens epithelium, a cell monolayer that covers the anterior hemisphere of the lens, are likely to be involved.

Materials and Methods: In this work, the lens epithelium has been analyzed for its DNA double-strand break (DSB) repair response to ionizing radiation. The responses of epithelial cells located at the anterior pole (central region) have been compared to at the very periphery of the monolayer (germinative and transitional zones). Described here are the different responses in the two regions and across four strains (C57BL/6, 129S2, BALB/c and CBA/Ca) over a low dose (0–25 mGy) in-vivo whole body X-irradiation range up to 24?hours post exposure.

Results: DNA damage and repair as visualized through 53BP1 staining was present across the lens epithelium, although repair kinetics appeared non-uniform. Epithelial cells in the central region have significantly more 53BP1 foci. The sensitivities of different mouse strains have also been compared.

Conclusions: 129S2 and BALB/c showed higher levels of DNA damage, with BALB/c showing significantly less inter-individual variability and appearing to be a more robust model for future DNA damage and repair studies. As a result of this study, BALB/c was identified as a suitable radiosensitive lens strain to detect and quantify early low dose ionizing radiation DNA damage effects in the mouse eye lens specifically, as an indicator of cataract formation.