鼻咽癌放疗抗拒性的蛋白质组学研究
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摘要
鼻咽癌(nasopharyngeal carcinoma, NPC)是我国南方常见的恶性肿瘤,其发病率和死亡率均居世界首位,严重威胁我国人民的生命和健康。放疗是NPC的主要治疗手段。虽然放疗设备和方法不断改进,但NPC疗效无明显改善。放疗失败的主要原因是NPC组织中存在一定比例的放疗抗拒细胞,放疗后残留的这些肿瘤细胞不仅放射抗拒性增强,而且更具侵袭性、容易发生淋巴结和远处转移。因此,放疗抗拒仍然是制约NPC疗效的瓶颈。但NPC放射抗拒的分子机制不太清楚。寻找NPC放射抗拒相关的蛋白质,不仅有助于揭示NPC放疗抗拒的机制,而且能为NPC放疗敏感性预测以及NPC的靶向和个体化治疗提供科学依据,对提高NPC的疗效、改善NPC预后具有重要作用。
为筛选NPC放疗抗拒相关的蛋白质,我们采用亚致死剂量放射线反复照射法建立了放射抗拒的NPC细胞株CNE2-IR,该细胞系来源于NPC细胞株CNE2,为接受5次亚致死剂量放射线(11Gy)照射后存活的亚克隆细胞。然后采用蛋白质组学技术比较放射抗拒CNE2-IR细胞与放射敏感CNE2细胞蛋白质表达谱的差异,筛选NPC的放疗抗拒相关蛋白质。即应用二维凝胶电泳(Two-dimensional gel electrophoresis,2-DE)分离两株细胞的总蛋白质,PDQuest软件分析识别差异表达蛋白质点,基质辅助激光解吸电离-飞行时间质谱(MALDI-TOF-MS)和电喷雾电离串联质谱(ESI-Q-TOF MS／MS)鉴定差异表达的蛋白质。Western blot对蛋白质组学筛选到的差异蛋白质进行验证。
建立了高质量的放射抗拒CNE2-IR细胞与放射敏感CNE2细胞的2-DE图谱,质谱共鉴定出34种差异表达的蛋白质。其中14-3-3σ和Maspin表达在放射抗拒的CNE2-IR细胞中明显下调,而GRP78和Mn-SOD表达明显上调。应用Western blot验证了4种蛋白质(14-3-3σ、Maspin、GRP78和Mn-SOD)在CNE2-IR和CNE2细胞株中的差异表达水平。
为了探讨差异表达蛋白质能否作为预测NPC放疗敏感性的分子标志,采用免疫组化检测差异蛋白14-3-3σ、Maspin、GRP78和Mn-SOD在39例放射抗拒和51例放射敏感NPC组织中的表达,采用ROC(Receiver Operating Characteristic, ROC)曲线分析4个蛋白质预测NPC放疗敏感性的价值。结果显示,与放疗敏感的NPC组织比较,14-3-3σ和Maspin表达在放射抗拒NPC组织中明显下调,而GRP78和Mn-SOD表达明显上调。14-3-3σ和Maspin表达下调,以及GRP78和Mn-SOD表达上调与NPC放射抗拒性有明显的相关性；4个蛋白质组合判别放射敏感与放射抗拒NPC的敏感性为90%、特异性为88%。
为进一步证实4个差异蛋白质在NPC放射抗拒产生中的作用,我们选择差异蛋白质14-3-3σ进行功能分析。既采用基因转染技术上调14-3-3σ在CNE2-IR细胞中的表达,采用克隆存活实验检测14-3-3σ表达上调对其放疗敏感性的影响。结果显示,14-3-3σ表达上调可部分逆转CNE2-IR细胞的放射抗拒性,这提示14-3-3σ在NPC放射抗拒产生中具有重要的作用。
本文研究结果表明,14-3-3σ、Maspin、GRP78和Mn-SOD蛋白是预测NPC放疗敏感性的潜在生物标志物,它们表达失调可能参与NPC放射抗拒性的产生。
Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in southern China with the highest incidence and mortality rate in the world. It poses one of the most serious public health problems in this area. Radiotherapy is the primary treatment for NPC. Although the radiotherapeutic equipments and technique are improved continuously, the radiotherapeutic efficacy of NPC remains unfavorable. The main reason for the failure of NPC radiotherapy is that there are a certain percentage of radioresistant cells in the NPC tissues, which not only have higher radioresistance, but also are more aggressive after radiotherapy, prone to lymph node and distant metastasis. Therefore, the radioresistance remains a serious obstacle to successful treatment in some NPC cases.However, the molecular mechanism underlying radioresistance of NPC has not been elucidated yet. The finding of radioresistant proteins will be useful for revealing the mechanism of NPC radioresistance, and providing the scientific basis for predicting NPC sensitivity as well as targets and personalized therapy, which plays an important role in improving efficacy and prognosis of NPC.
To identify proteins involved in NPC resistance, we established a radioresistant subclone cell line (CNE2-IR) derived from NPC cell line CNE2 by treating the cells with five rounds of sublethal ionizing radiation (11Gy). Proteomics was then performed to compare protein profiles of CNE2-IR and CNE2 cells. Two-dimensional gel electrophoresis (2-DE) was performed to separate the total proteins of CNE2-IR and CNE2 cells, PDQuest software was applied to analyze the differential protein spots between the CNE2-IR and CNE2 cell lines, these differential spots were identified by both MALDI-TOF-MS and ESI-Q-TOF-MS,and the differential proteins identified by proteomic approach were confirmed by Western blot.
Highly reproductive and resolvable 2-DE maps of CNE2-IR and CNE2 cells were established. A total of 34 differential proteins was identified by MALDI-TOF MS and ESI-Q-TOF MS.Among them,14-3-3σand Maspin was significantly downregulated, and GRP78 and Mn-SOD was significantly upregulated in the radioresistant CNE2-IR as compared with control CNE2. The differential expression levels of the four proteins (14-3-3σ, Maspin, GRP78 and Mn-SOD) between the CNE2-IR and CNE2 cell lines were confirmed by Western blot.
To investigate whether the differentially expressed proteins serve as predictive molecular markers for radiosensitivity of NPC, immunohistochemistry was performed to detect the expression levels of 14-3-3σ, Maspin, GRP78 and Mn-SOD proteins in the 39 radioresistant and 51 radiosensitive NPC tissues. The ability of 14-3-3σ, Maspin, GRP78 and Mn-SOD in distinguishing the radiosensitive and radioresistant NPC tissues was evaluated by the ROC (receiver operating characteristic) analysis. The results showed that 14-3-3σand Maspin was significantly downregulated, and GRP78 and Mn-SOD was significantly upregulated in the radioresistant NPC tissues as compared with radiosensitive NPC tissues.The downregulation of 14-3-3σand Maspin and upregulation of Mn-SOD and GRP78 were significantly correlated with NPC radioresistance.As a panel, the four proteins achieved a sensitivity of 90% and a specificity of 88% in discriminating radiosensitive from radioresistant NPC.
To address the question whether the expression levels of the four proteins may associate with the development of NPC radioresistance, we selected 14-3-3σ, one of the four differential proteins to be further functionally studied. pcDNA3-14-3-3σplasmid was transfected into the CNE-2-IR cells to upregulate the expression of 14-3-3σ, and the effect of 14-3-3σ-upregulation on CNE-2-IR radiosensitivity was measured by using a clonogenic survival assay. The results indicated that the radioresistance can be partially reversed by overexpression of 14-3-3σin the CNE2-IR cells.
Our data showed that 14-3-3σ, Maspin, GRP78 and Mn-SOD proteins are potential biomarkers for predicting NPC radiosensitivity.Their dysregulation may be involved in the development of NPC radioresistance.
为筛选NPC放疗抗拒相关的蛋白质,我们采用亚致死剂量放射线反复照射法建立了放射抗拒的NPC细胞株CNE2-IR,该细胞系来源于NPC细胞株CNE2,为接受5次亚致死剂量放射线(11Gy)照射后存活的亚克隆细胞。然后采用蛋白质组学技术比较放射抗拒CNE2-IR细胞与放射敏感CNE2细胞蛋白质表达谱的差异,筛选NPC的放疗抗拒相关蛋白质。即应用二维凝胶电泳(Two-dimensional gel electrophoresis,2-DE)分离两株细胞的总蛋白质,PDQuest软件分析识别差异表达蛋白质点,基质辅助激光解吸电离-飞行时间质谱(MALDI-TOF-MS)和电喷雾电离串联质谱(ESI-Q-TOF MS／MS)鉴定差异表达的蛋白质。Western blot对蛋白质组学筛选到的差异蛋白质进行验证。
建立了高质量的放射抗拒CNE2-IR细胞与放射敏感CNE2细胞的2-DE图谱,质谱共鉴定出34种差异表达的蛋白质。其中14-3-3σ和Maspin表达在放射抗拒的CNE2-IR细胞中明显下调,而GRP78和Mn-SOD表达明显上调。应用Western blot验证了4种蛋白质(14-3-3σ、Maspin、GRP78和Mn-SOD)在CNE2-IR和CNE2细胞株中的差异表达水平。
为了探讨差异表达蛋白质能否作为预测NPC放疗敏感性的分子标志,采用免疫组化检测差异蛋白14-3-3σ、Maspin、GRP78和Mn-SOD在39例放射抗拒和51例放射敏感NPC组织中的表达,采用ROC(Receiver Operating Characteristic, ROC)曲线分析4个蛋白质预测NPC放疗敏感性的价值。结果显示,与放疗敏感的NPC组织比较,14-3-3σ和Maspin表达在放射抗拒NPC组织中明显下调,而GRP78和Mn-SOD表达明显上调。14-3-3σ和Maspin表达下调,以及GRP78和Mn-SOD表达上调与NPC放射抗拒性有明显的相关性；4个蛋白质组合判别放射敏感与放射抗拒NPC的敏感性为90%、特异性为88%。
为进一步证实4个差异蛋白质在NPC放射抗拒产生中的作用,我们选择差异蛋白质14-3-3σ进行功能分析。既采用基因转染技术上调14-3-3σ在CNE2-IR细胞中的表达,采用克隆存活实验检测14-3-3σ表达上调对其放疗敏感性的影响。结果显示,14-3-3σ表达上调可部分逆转CNE2-IR细胞的放射抗拒性,这提示14-3-3σ在NPC放射抗拒产生中具有重要的作用。
本文研究结果表明,14-3-3σ、Maspin、GRP78和Mn-SOD蛋白是预测NPC放疗敏感性的潜在生物标志物,它们表达失调可能参与NPC放射抗拒性的产生。
Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in southern China with the highest incidence and mortality rate in the world. It poses one of the most serious public health problems in this area. Radiotherapy is the primary treatment for NPC. Although the radiotherapeutic equipments and technique are improved continuously, the radiotherapeutic efficacy of NPC remains unfavorable. The main reason for the failure of NPC radiotherapy is that there are a certain percentage of radioresistant cells in the NPC tissues, which not only have higher radioresistance, but also are more aggressive after radiotherapy, prone to lymph node and distant metastasis. Therefore, the radioresistance remains a serious obstacle to successful treatment in some NPC cases.However, the molecular mechanism underlying radioresistance of NPC has not been elucidated yet. The finding of radioresistant proteins will be useful for revealing the mechanism of NPC radioresistance, and providing the scientific basis for predicting NPC sensitivity as well as targets and personalized therapy, which plays an important role in improving efficacy and prognosis of NPC.
To identify proteins involved in NPC resistance, we established a radioresistant subclone cell line (CNE2-IR) derived from NPC cell line CNE2 by treating the cells with five rounds of sublethal ionizing radiation (11Gy). Proteomics was then performed to compare protein profiles of CNE2-IR and CNE2 cells. Two-dimensional gel electrophoresis (2-DE) was performed to separate the total proteins of CNE2-IR and CNE2 cells, PDQuest software was applied to analyze the differential protein spots between the CNE2-IR and CNE2 cell lines, these differential spots were identified by both MALDI-TOF-MS and ESI-Q-TOF-MS,and the differential proteins identified by proteomic approach were confirmed by Western blot.
Highly reproductive and resolvable 2-DE maps of CNE2-IR and CNE2 cells were established. A total of 34 differential proteins was identified by MALDI-TOF MS and ESI-Q-TOF MS.Among them,14-3-3σand Maspin was significantly downregulated, and GRP78 and Mn-SOD was significantly upregulated in the radioresistant CNE2-IR as compared with control CNE2. The differential expression levels of the four proteins (14-3-3σ, Maspin, GRP78 and Mn-SOD) between the CNE2-IR and CNE2 cell lines were confirmed by Western blot.
To investigate whether the differentially expressed proteins serve as predictive molecular markers for radiosensitivity of NPC, immunohistochemistry was performed to detect the expression levels of 14-3-3σ, Maspin, GRP78 and Mn-SOD proteins in the 39 radioresistant and 51 radiosensitive NPC tissues. The ability of 14-3-3σ, Maspin, GRP78 and Mn-SOD in distinguishing the radiosensitive and radioresistant NPC tissues was evaluated by the ROC (receiver operating characteristic) analysis. The results showed that 14-3-3σand Maspin was significantly downregulated, and GRP78 and Mn-SOD was significantly upregulated in the radioresistant NPC tissues as compared with radiosensitive NPC tissues.The downregulation of 14-3-3σand Maspin and upregulation of Mn-SOD and GRP78 were significantly correlated with NPC radioresistance.As a panel, the four proteins achieved a sensitivity of 90% and a specificity of 88% in discriminating radiosensitive from radioresistant NPC.
To address the question whether the expression levels of the four proteins may associate with the development of NPC radioresistance, we selected 14-3-3σ, one of the four differential proteins to be further functionally studied. pcDNA3-14-3-3σplasmid was transfected into the CNE-2-IR cells to upregulate the expression of 14-3-3σ, and the effect of 14-3-3σ-upregulation on CNE-2-IR radiosensitivity was measured by using a clonogenic survival assay. The results indicated that the radioresistance can be partially reversed by overexpression of 14-3-3σin the CNE2-IR cells.
Our data showed that 14-3-3σ, Maspin, GRP78 and Mn-SOD proteins are potential biomarkers for predicting NPC radiosensitivity.Their dysregulation may be involved in the development of NPC radioresistance.
引文
[1]Chua DT, Ma J, Sham JS, et al. Improvement of survival after addition of induction chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma:Subgroup analysis of two Phase Ⅲ trials[J]. Int J Radiat Oncol Biol Phys,2006;65(5):1300-1306
[2]Chua DT, Sham JS, Hunq KN, et al. Predictive factors of tumor control and survival after radiosurgery for local failures of nasopharyngeal carcinoma[J]. Int J Radiat Oncol Biol Phys,2006;66(5):1415-1421
[3]刘秀芳,夏云飞.鼻咽癌放射敏感性的分子生物学实验[A].见：夏云飞,钱剑扬主编.实用鼻咽癌放射治疗学[M].第1版.北京：北京大学医学出版社,2003.211-214.
[4]Olive PL. DNA damage and repair in individual cells:applications of the comet assay in radiobiology.Int J Radiat Biol,1999;75:395-405.
[5]Peggy L Olive, Judit P Banath. The comet assay:a method to measure DNA damage in individual cells. NATURE PROTOCOLS,2006;1(1):23-29
[6]闫洁,杨伟志.“彗星”分析法及应用.中华放射肿瘤学杂志.2002,11：66-68.
[7]高远红,杨伟志,闫洁,等.“彗星”分析法检测人癌裸鼠移植瘤的放射敏感性.中华放射肿瘤学杂志,2004,13(1)：48-51.
[8]Schwartz JL, Mustafi R, Beckett MA, et al. Prediction of the radiation sensitivity of human squamous cell carcinoma cells using DNA filter elution. Radiat Res,1990;123(1):1-6.
[9]Nunez MI,Guerrero MR,Lopez E,et al.DNA damage and prediction of radiation response in lymphocytes and epidermal skin human cells [J].Int J Cancer,1998;76(3):354-361.
[10]高黎,杨伟志,袁智勇,等.改良“彗星”分析法检测鼻咽癌放射敏感性的初步研究.中华放射肿瘤学杂志,2004,13(1)：39-43
[11]张玉晶,闫洁,高远红,等.中性彗星分析法检测肿瘤细胞的放射敏感性.中国肿瘤,2004,13(11)：731-734
[12]Ando N, Nakajima T, Masuda H, et al.Antimicrotubule effects of the novel anti-tumor benzoylphenylurea derivative HO-221.Carcer Chemother Pharmacol,1995;37 (1/2):63-68
[13]Johnson RT, Rao PN.Mammalian cell fusion:induction of premature chromosome condensation in interphase nuclei.Nature,1970;226 (5247):717-722.
[14]Suzuki M, Kase Y.Correlation between cell death and induction of non-rejoining pcc breaks by carbon-ion beams.Adv Space Res,1998; 22:561-568.
[15]Andreassen CN, Alsner J, Overgaard M.Prediction of normal tissue radiosensitivity from polymorphisms in candidate genes. Radiother Oncol, 2003;69(2):127-135.
[16]Achary MP, Jaggernauth W, Gross E, et al.Cell lines from the same cervical carcinoma but with different radiosensitivities exhibit different cDNA microarray patterns of gene expression.Cytogenet Cell Genet,2000; 91(1-4): 39-43.
[17]Chang JT, Chan SH, Lin CY, et al.Differentially expressed genes in radioresistant nasopharyngeal cancer cells:gp96 and GDF15.Mol Cancer Ther 2007;6:2271-9.
[18]Kitahara O,Katagiri T,Tsunoda T,et al. Classification of sensitivity or resistance of cervical cancers to ionizing radiation according to expression profiles of 62 genes selected by cDNA microarray analysis. Neoplasia, 2002;4(4):295-303
[19]Hanna E, Shrieve DC, Ratanatharathorn V, et al. A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck. Cancer Res,2001;61(6):2376-2380.
[20]Yu M C, Yuan J M. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol,2002; 12(6):421-429
[21]Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet,2005;365 (9476): 2041-2054
[22]Pearce AG,Segura TM,Rintala AC,et al.The generation and characterization of a radiation-resistant model system to study radioresistance in human breast cancer cells.Radiat Res,2001; 156:739-750.
[23]Wei K,Kodym R,Jin C.Radioresistant cell strain of human fibrosarcoma cells obtained after long-term exposure to X-rays. Radiat Environ Biophys,1998;37:133-137.
[24]Russell J,Wheidon TE,Stanton P. A radioresistant variant derived from a humanneuroblastoma cell line is less prone to radiation-induced apoptosis. Cancer Res,1995;55:4915-4921.
[25]魏启春,郑树.放射抗拒肺癌细胞亚系D62R的建立及其细胞周期研究.中华放射医学与防护杂志2003,23(4)：267-269.
[26]Srzen F,Nilsson A,Zhivotovsky B,et al.DNA-dependent protein kinase content and activity in lung carcinoma cell lines :correlation with intrinsic radiosensitivity. Euro J Cancer,1999;35:111-116.
[27]Russell J,Wheidon TE,Stanton P. A radioresistant variant derived from a humanneuroblastoma cell line is less prone to radiation-induced apoptosis. Cancer Res,1995;55:4915-4921.
[28]夏云飞,李满枝,黄冰,等.14株(亚株)人鼻咽癌细胞的放射生物特性.癌症,2001,20(7)：683-687.
[29]石慧英,孙懿,易红,冯雪萍,陈主初,肖志强.p53沉默对人鼻咽癌细胞株CNE2放射生物学特性的影响.国际病理科学与临床杂志,2008,28(2)：97-102
[30]王亚利,王西京,王中卫,金迎迎,李毅.放射抗拒性鼻咽癌细胞系的建立及差异表达基因.西安交通大学学报(医学版),2009,30(6)：741-745,748.
[31]Murray D,McEwan AJ.Radiobiology of systemic radiation them-PY. Cancer Biother Radiopharm。2007;22:1-23.
[32]Mitsubashi N, Takahashi T, Sakurai H, et al. A radioresistant variant cell line. NMT—1R. isolated from a radiosensitive rat yolk sactumour cell line. NMT.1:differences of early radiation—induced morphological changes, especially apoptosis. Int J Radiat Biol,1996;69:329-336.
[33]许庆勇,徐向英,杨伟志.X线反复照射人肺癌细胞系Anip973后的生物特性变化.中华放射肿瘤学杂志,2008,17：51-54.
[34]董刚,汪成林,彭栗,等.毛囊bulge干细胞培养方法的比较研究.实用医学杂志,2009,25(10):1550-1552.
[35]Tyessier F,Bay JO,Dionet C,et al.Cell cycle regulation after exposure to ionizing radiation.Bull Cancer,1999;86:3452357.
[36]Hunakova L,Chorvath M,Duraj J,et al.Radiation induced apoptosis and cell cycle alterations in human carcinoma cell lines with different radiosensitivities.Neoplasma,2000;47:25231.
[37]冯雪萍,陈主初,肖志强,等.NM23-H1、DJ1和TIM1在低分化鼻咽鳞癌组织和CNE2细胞株中共同表达.生物化学与生物物理进展,2005,32(4)：338.346
[38]Sun Y, Yi H, Zhang PF, et al.Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis. FEBS Lett,2007;581(1):131-139
[39]Li F, Xiao Z, Zhang P,et al.A reference map of human nasopharyngeal squamous carcinoma proteome. Int J Oncol,2007;30(5):1077-1088
[40]Clauser KR, Baker P,Burlingame AL. Role of accurate mass measurement (+/-10 ppm) in protein identification strategies employing MS or MS/MS and database searching.Anal Chem,1999;71(14):2871-2882.
[41]Perkins DN, Pappin DJ, Creasy DM,et al.Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis,1999;20(18):3551-3567.
[42]Zhang W,Chait BT.ProFound:an expert system for protein identification using mass spectrometric peptide mapping information. Anal Chem,2000;72(11):2482-2489.
[43]Ding Q, Xiao L, Xiong S, Unmatched masses in peptide mass fingerprints caused by cross-contamination:an updated statistical result. Proteomics. 2003;3(7):1313-1317.
[44]张丽珍,程炳权,杨伟志.CNA及nm23的表达与食管鳞癌放射敏感性及预后的相关性研究.中华放射肿瘤学杂志,2001,10(4)：239-242
[45]王红梅,伍新荛,夏云飞等.ATM在不同放射敏感性鼻咽癌细胞株中表达.癌症,2003,22(6)：579-581.
[46]Sang M, Li Y, Ozaki T,et al. p73-dependent induction of 14-3-3sigma increases the chemo-sensitivity of drug-resistant human breast cancers. Biochem Biophys Res Commun 2006;347:327-33.
[47]Marioni G, Koussis H, Gaio E,et al.MASPIN's prognostic role in patients with advanced head and neck carcinoma treated with primary chemotherapy (carboplatin plus vinorelbine) and radiotherapy:preliminary evidence.Acta Otolaryngol 2009; 129:786-92.
[48]Lee E, Nichols P, Spicer D,et al.GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer.Cancer Res 2006; 66:7849-53
[49]Suresh A,Tung F,Moreb J,et al. Role of manganese superoxide dismutase in radioprotection using gene transfer studies. Cancer Gene Ther 1994; 1:85-90.
[50]Hu S, Arellano M, Boontheung P, et al. Salivary Proteomics for Oral Cancer Biomarker Discovery.Clin Cancer Res 2008; 14:6246-52.
[51]Lee AW, Poon YF, Foo W, et al. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985:overall survival and patterns of failure.Int J Radiat Oncol Biol Phys 1992;23:261-70.
[52]Leung SF, Teo PM, Shiu WW, et al. Clinical features and management of distant metastases of nasopharyngeal carcinoma. J Otolaryngol 1991;20:27-9.
[53]Mhawech P.14-3-3 proteins--an update. Cell Res 2005;15:228-36.
[54]Laronga C,Yang HY,Neal C,Lee MH. Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates cell cycle progression. J Biol Chem 2000;275:23106-12.
[55]Yang HY, Wen YY, Chen CH, Lozano G,Lee MH.14-3-3 sigma positively regulates p53 and suppresses tumor growth.Mol Cell Biol 2003; 23:7096-107.
[56]Gudkov AV, Komarova EA.The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer 2003;3:117-29.
[57]Sang M, Li Y, Ozaki T,et al.p73-dependent induction of 14-3-3sigma increases the chemo-sensitivity of drug-resistant human breast cancers. Biochem Biophys Res Commun 2006;347:327-33.
[58]Cheng AL,Huang WG,Chen ZC,et al.Identification of novel nasopharyngeal carcinoma biomarkers by laser capture microdissection and proteomic analysis. Clin Cancer Res 2008; 14:435-45.
[59]Sager R, Sheng S, Pemberton P, et al. Maspin. A tumor suppressing serpin.Adv Exp Med Biol 1997;425:77-88.
[60]Sheng S.The promise and challenge toward the clinical application of maspin in cancer.Front Biosci 2004;9:2733-45.
[61]Schaefer JS, Zhang M. Targeting maspin in endothelial cells to induce cell apoptosis. Expert Opin Ther Targets 2006; 10:401-8.
[62]Mhawech-Fauceglia P, Dulguerov P, Beck A, et al.Value of ezrin,maspin and nm23-H1 protein expressions in predicting outcome of patients with head and neck squamous-cell carcinoma treated with radical radiotherapy. J Clin Pathol 2007;60:185-9.
[63]Sheng S. A role of novel serpin maspin in tumor progression:the divergence revealed through efforts to converge. J Cell Physiol 2006; 209:631-5.
[64]Lee AS. The glucose-regulated proteins:stress induction and clinical applications.Trends Biochem Sci 2001;26:504-10.
[65]Hendershot LM. The ER function BiP is a master regulator of ER function. MtSinai J Med 2004;71:289-97.
[66]Dong D, Dubeau L, Bading J, et al. Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors. Hum Gene Ther 2004; 15:553-61.
[67]Zhai L, Kita K, Wano C, Wu Y, Sugaya S, Suzuki N. Decreased cell survival and DNA repair capacity after UVC irradiation in association with down-regulation of GRP78/BiP in human RSa cells. Exp Cell Res 2005;305:244-52.
[68]Li J, Lee AS. Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 2006;6:45-54.
[69]顾永清.SOD及其在生物学中的应用[J].生物学通报,1993,28：8-11.
[70]Church SL,Grant JW, Ridnour LA,et al. Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells[J].Proc Natl Acad Sci USA,1993;90:3113-3117.
[71]Urano M,Kuroda M,Reynolds R,et al.Expression of manganese uperoxide dismutase reduces tumor control radiation dose:gene-radiotherapy[J].Cancer Res,1995;55:2490-2493.
[72]Safford SE, Oberley TD, Urano M, et al. Suppression of fibrosarcoma metastasis by elevated expression of manganese superoxide dismutase[J].Cancer Res,1994;54:4261-4265.
[73]Sun J, Chen Y, Li M, Ge Z. Role of antioxidant enzymes on ionizing radiation resistance. Free Radic Biol Med 1998;24:586-93.
[74]Rhee SG, Kim KH, Chae HZ,et al.Antioxidant defense mechanisms:a newthiol-specific antioxidant enzyme.Ann N Y Acad Sci 1994; 738:86-92.
[75]Epperly MW, Epstein CJ, Travis EL,et al.Decreased pulmonary radiation resistance of manganese superoxide dismutase (MnSOD)-deficient mice is corrected by human manganese superoxide dismutase-Plasmid/Liposome (SOD2-PL) intratracheal gene therapy. Radiat Res 2000; 154:365-74.
[76]Ozeki M, Tamae D, Hou DX, et al. Response of cyclin B1 to ionizing radiation:regulation by NF-kappaB and mitochondrial antioxidant enzyme MnSOD.Anticancer Res 2004;24:2657-63.
[77]Kalen AL,Sarsour EH,Venkataraman S,et al.Mn-superoxide dismutase overexpression enhances G2 accumulation and radioresistance in human oral squamous carcinoma cells. Antioxid Redox Signal 2006;8:1273-81
[1]Andreassen CN, Alsner J, Overgaard M. Prediction of normal tissue radiosensitivity from polymorphisms in candidate genes. Radiother Oncol, 2003,69(2):127-135.
[2]Baumann M, Holscher T, Begg AC. Towards genetic prediction of radiation responses:ESTRO's GENEPI project. Radiother Oncol,2003,69(2):121-125.
[3]Olive PL. DNA damage and repair in individual cells:applications of the comet assay in radiobiology. Int J Radiat Biol,1999,75:3952405.
[4]Peggy L Olive, Judit P Banath. The comet assay:a method to measure DNA damage in individual cells. NATURE PROTOCOLS,2006,1 (.1):23-29
[5]闫洁,杨伟志.“彗星”分析法及应用.中华放射肿瘤学杂志.2002,11：66-68.
[6]高远红,杨伟志,闫洁,袁智勇,刘新帆,徐国镇.“彗星”分析法检测人癌裸鼠移植瘤的放射敏感性.中华放射肿瘤学杂志,2004,13(1)：48-51.
[7]Schwartz JL, Mustafi R, Beckett MA, et al. Prediction of the radiation sensitivity of human squamous cell carcinoma cells using DNA filter elution. Radiat Res,1990,123(1):1-6.
[8]Nunez MI, Guerrero MR, Lopez E, et al. DNA damage and prediction of radiation response in lymphocytes and epidermal skin human cells. Int J Cancer, 1998,76(3):354-361.
[9]高黎,杨伟志,袁智勇,徐国镇,高远红,王冕荣.改良.“彗星”分析法检测鼻咽癌放射敏感性的初步研究.中华放射肿瘤学杂志,2004,13(1)：39-43
[10]张玉晶,闫洁,高远红,李艳春,杨伟志.中性彗星分析法检测肿瘤细胞的放射敏感性.中国肿瘤,2004,13(11)：731-734
[11]Ando N, Nakajima T, Masuda H, et al.Antimicrotubule effects of the novel anti-tumor benzoylphenylurea derivative HO-221. Carcer Chemother Pharmacol,1995,37:63
[12]Johnson RT, Rao PN.Mammalian cell fusion:induction of premature chromosome condensation in interphase nuclei.Nature,1970,226 (5247):717-722.
[13]Suzuki M, Kase Y.Correlation between cell death and induction of non-rejoining pcc breaks by carbon-ion beams.Adv Space Res,1998, 22:561-568.
[14]夏云飞,李满枝,黄冰,等.14株(亚株)人鼻咽癌细胞的放射生物特性.癌症,2001,20(7)：683 687.
[15]石慧英,孙懿,易红,冯雪萍,陈主初,肖志强.p53沉默对人鼻咽癌细胞株CNE2放射生物学特性的影响.国际病理科学与临床杂志,2008,28(2)：97-102
[16]王亚利,王西京,王中卫,金迎迎,李毅.放射抗拒性鼻咽癌细胞系的建立及差异表达基因.西安交通大学学报(医学版),2009,30(6)：741-745,748.
[17]冯雪萍,刘伟,肖志强,黄生鹏,李建玲,易红,张鹏飞,段朝军.近致死量照射CNE1后存活克隆生物学性状初步分析.中国耳鼻咽喉颅底外科杂志,2007,13(4)：245-249.
[18]冯雪萍,陈主初,肖志强,易红,李建玲,杨轶轩.放疗诱导鼻咽癌细胞株CNE1热休克蛋白高表达.中国耳鼻咽喉颅底外科杂志,2005,11(2)：81-84.
[19]Achary MP, Jaggernauth W, Gross E, et al. Cell lines from the same cervical carcinoma but with different radiosensitivities exhibit different cDNA microarray patterns of gene expression. Cytogenet Cell Genet,2000, 91(1-4):39-43.
[20]Hanna E, Shrieve DC, Ratanatharathorn V, et al. A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck. Cancer Res,2001,61(6):2376-2380.
[21]Pusztai L, Ayers M, Stec J, et al. Clinical application of cDNA microarrays in oncology. Oncologist,2003,8(3):252-258.
[22]Harima Y, Sawada S, Miyazaki Y, et al. Expression of Ku80 in cervical cancer correlates with response to radiotherapy and survival. Am J Clin Oncol,2003, 26 (4):e80-85.
[23]Hasan RK, Wulfkuhle JD, Liotta LA, et al. STUDENTJAMA.Molecular technologies for personalized cancer management[J]. JAMA,2004, 291(13):1644-1645.
[24]Mian S, Ball G, Hornbuckle J, et al. A prototype methodology combining surface-enhanced laser desorption/ionization protein chip technology and artificial neural network algorithms to predict the chemoresponsiveness of breast cancer cell lines exposed to Paclitaxel and Doxorubicin under in vitro conditions[J].Proteomics,2003,3(9):1725-1737.
[25]Hagen JB. The origins of bioinformatics. Nat Rev Genet,2000,1 (3):231-6.
[26]沈瑜,肖海洁.肿瘤放射增敏剂在肿瘤放射治疗中的应用[J].中华肿瘤杂志,1999,21(3)：233-234
[27]蔡芸,陈志龙,赵芳,等.硝基咪唑类抗肿瘤放射增敏剂研究进展[J].中国新药杂志,2003,12(4)：249-252
[28]孙晋瑞,冯光玲,国大亮.肿瘤放疗增敏剂---甘氨双唑钠[J].齐鲁药事,2004,23(1)：32-35
[29]周厚清,邢成,李伯南.肿瘤放射增敏剂及增敏机制研究进展[J].国外医学·肿瘤学分册,2001,28(6)：756-751
[30]Pauwels B,Korst AE,dePooter CM,etal.The radiosensitising effect of gemcitabine and the influence of the rescue agent amifostine in vitro [J].Eur J Cancer,2003,39 (6):838-846
[31]陈晓晶,金一尊.生物还原剂的作用机理研究概况[J].辐射研究与辐射工艺学报,2003,21(2)：83-87
[32]Craighead P S,Pearcey R,Stuart G.A phase Ⅰ/Ⅱ evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer[J].Int J Radiat Oncol BiolPhys,2000,48(3):791-795
[33]Kasid U,Dritschilo A.RAF antisense oligonuclectide as a tumor radiosensitizer[J].Oncogene,2003,22(37):5876-5884
[34]刘琳,王锦鸿.中药对放射治疗增敏作用的研究概况[J].南京中医药大学学报,1999,15(1)：63-64
[35]李勤,谢艳华,孙纪元,等.中药安迪注射剂对人食管癌细胞的放射增敏作用[J].中国药科大学学报,2003,34(4)：356-358
[36]Lu J,Shao H.Survey on natural radiosensitizing agents since 2000 [J].J Chin Phar Sci,2003,12 (3):160-163
[37]Cecchini S,Girouard MA, Huels L,et al.Single-strand-specific radiosensitization of DNA by bromodeoxyuridine [J].Radiat Res,2004,162 (6):604-615
[38]李莉.放射增敏剂研究概况[J].国外医学·放射医学核医学分册,2001,25(2)：87-89
[39]罗波,于世英,庄亮,等.AG825对乳腺癌细胞的辐射增敏作用.中国肿瘤临床,2008,35(19)：1131-1134.
[40]郑秀龙,金一尊,沈瑜,等.肿瘤治疗增敏药.上海：上海科学技术文献出版社,2002：1014.
[2]Chua DT, Sham JS, Hunq KN, et al. Predictive factors of tumor control and survival after radiosurgery for local failures of nasopharyngeal carcinoma[J]. Int J Radiat Oncol Biol Phys,2006;66(5):1415-1421
[3]刘秀芳,夏云飞.鼻咽癌放射敏感性的分子生物学实验[A].见：夏云飞,钱剑扬主编.实用鼻咽癌放射治疗学[M].第1版.北京：北京大学医学出版社,2003.211-214.
[4]Olive PL. DNA damage and repair in individual cells:applications of the comet assay in radiobiology.Int J Radiat Biol,1999;75:395-405.
[5]Peggy L Olive, Judit P Banath. The comet assay:a method to measure DNA damage in individual cells. NATURE PROTOCOLS,2006;1(1):23-29
[6]闫洁,杨伟志.“彗星”分析法及应用.中华放射肿瘤学杂志.2002,11：66-68.
[7]高远红,杨伟志,闫洁,等.“彗星”分析法检测人癌裸鼠移植瘤的放射敏感性.中华放射肿瘤学杂志,2004,13(1)：48-51.
[8]Schwartz JL, Mustafi R, Beckett MA, et al. Prediction of the radiation sensitivity of human squamous cell carcinoma cells using DNA filter elution. Radiat Res,1990;123(1):1-6.
[9]Nunez MI,Guerrero MR,Lopez E,et al.DNA damage and prediction of radiation response in lymphocytes and epidermal skin human cells [J].Int J Cancer,1998;76(3):354-361.
[10]高黎,杨伟志,袁智勇,等.改良“彗星”分析法检测鼻咽癌放射敏感性的初步研究.中华放射肿瘤学杂志,2004,13(1)：39-43
[11]张玉晶,闫洁,高远红,等.中性彗星分析法检测肿瘤细胞的放射敏感性.中国肿瘤,2004,13(11)：731-734
[12]Ando N, Nakajima T, Masuda H, et al.Antimicrotubule effects of the novel anti-tumor benzoylphenylurea derivative HO-221.Carcer Chemother Pharmacol,1995;37 (1/2):63-68
[13]Johnson RT, Rao PN.Mammalian cell fusion:induction of premature chromosome condensation in interphase nuclei.Nature,1970;226 (5247):717-722.
[14]Suzuki M, Kase Y.Correlation between cell death and induction of non-rejoining pcc breaks by carbon-ion beams.Adv Space Res,1998; 22:561-568.
[15]Andreassen CN, Alsner J, Overgaard M.Prediction of normal tissue radiosensitivity from polymorphisms in candidate genes. Radiother Oncol, 2003;69(2):127-135.
[16]Achary MP, Jaggernauth W, Gross E, et al.Cell lines from the same cervical carcinoma but with different radiosensitivities exhibit different cDNA microarray patterns of gene expression.Cytogenet Cell Genet,2000; 91(1-4): 39-43.
[17]Chang JT, Chan SH, Lin CY, et al.Differentially expressed genes in radioresistant nasopharyngeal cancer cells:gp96 and GDF15.Mol Cancer Ther 2007;6:2271-9.
[18]Kitahara O,Katagiri T,Tsunoda T,et al. Classification of sensitivity or resistance of cervical cancers to ionizing radiation according to expression profiles of 62 genes selected by cDNA microarray analysis. Neoplasia, 2002;4(4):295-303
[19]Hanna E, Shrieve DC, Ratanatharathorn V, et al. A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck. Cancer Res,2001;61(6):2376-2380.
[20]Yu M C, Yuan J M. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol,2002; 12(6):421-429
[21]Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet,2005;365 (9476): 2041-2054
[22]Pearce AG,Segura TM,Rintala AC,et al.The generation and characterization of a radiation-resistant model system to study radioresistance in human breast cancer cells.Radiat Res,2001; 156:739-750.
[23]Wei K,Kodym R,Jin C.Radioresistant cell strain of human fibrosarcoma cells obtained after long-term exposure to X-rays. Radiat Environ Biophys,1998;37:133-137.
[24]Russell J,Wheidon TE,Stanton P. A radioresistant variant derived from a humanneuroblastoma cell line is less prone to radiation-induced apoptosis. Cancer Res,1995;55:4915-4921.
[25]魏启春,郑树.放射抗拒肺癌细胞亚系D62R的建立及其细胞周期研究.中华放射医学与防护杂志2003,23(4)：267-269.
[26]Srzen F,Nilsson A,Zhivotovsky B,et al.DNA-dependent protein kinase content and activity in lung carcinoma cell lines :correlation with intrinsic radiosensitivity. Euro J Cancer,1999;35:111-116.
[27]Russell J,Wheidon TE,Stanton P. A radioresistant variant derived from a humanneuroblastoma cell line is less prone to radiation-induced apoptosis. Cancer Res,1995;55:4915-4921.
[28]夏云飞,李满枝,黄冰,等.14株(亚株)人鼻咽癌细胞的放射生物特性.癌症,2001,20(7)：683-687.
[29]石慧英,孙懿,易红,冯雪萍,陈主初,肖志强.p53沉默对人鼻咽癌细胞株CNE2放射生物学特性的影响.国际病理科学与临床杂志,2008,28(2)：97-102
[30]王亚利,王西京,王中卫,金迎迎,李毅.放射抗拒性鼻咽癌细胞系的建立及差异表达基因.西安交通大学学报(医学版),2009,30(6)：741-745,748.
[31]Murray D,McEwan AJ.Radiobiology of systemic radiation them-PY. Cancer Biother Radiopharm。2007;22:1-23.
[32]Mitsubashi N, Takahashi T, Sakurai H, et al. A radioresistant variant cell line. NMT—1R. isolated from a radiosensitive rat yolk sactumour cell line. NMT.1:differences of early radiation—induced morphological changes, especially apoptosis. Int J Radiat Biol,1996;69:329-336.
[33]许庆勇,徐向英,杨伟志.X线反复照射人肺癌细胞系Anip973后的生物特性变化.中华放射肿瘤学杂志,2008,17：51-54.
[34]董刚,汪成林,彭栗,等.毛囊bulge干细胞培养方法的比较研究.实用医学杂志,2009,25(10):1550-1552.
[35]Tyessier F,Bay JO,Dionet C,et al.Cell cycle regulation after exposure to ionizing radiation.Bull Cancer,1999;86:3452357.
[36]Hunakova L,Chorvath M,Duraj J,et al.Radiation induced apoptosis and cell cycle alterations in human carcinoma cell lines with different radiosensitivities.Neoplasma,2000;47:25231.
[37]冯雪萍,陈主初,肖志强,等.NM23-H1、DJ1和TIM1在低分化鼻咽鳞癌组织和CNE2细胞株中共同表达.生物化学与生物物理进展,2005,32(4)：338.346
[38]Sun Y, Yi H, Zhang PF, et al.Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis. FEBS Lett,2007;581(1):131-139
[39]Li F, Xiao Z, Zhang P,et al.A reference map of human nasopharyngeal squamous carcinoma proteome. Int J Oncol,2007;30(5):1077-1088
[40]Clauser KR, Baker P,Burlingame AL. Role of accurate mass measurement (+/-10 ppm) in protein identification strategies employing MS or MS/MS and database searching.Anal Chem,1999;71(14):2871-2882.
[41]Perkins DN, Pappin DJ, Creasy DM,et al.Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis,1999;20(18):3551-3567.
[42]Zhang W,Chait BT.ProFound:an expert system for protein identification using mass spectrometric peptide mapping information. Anal Chem,2000;72(11):2482-2489.
[43]Ding Q, Xiao L, Xiong S, Unmatched masses in peptide mass fingerprints caused by cross-contamination:an updated statistical result. Proteomics. 2003;3(7):1313-1317.
[44]张丽珍,程炳权,杨伟志.CNA及nm23的表达与食管鳞癌放射敏感性及预后的相关性研究.中华放射肿瘤学杂志,2001,10(4)：239-242
[45]王红梅,伍新荛,夏云飞等.ATM在不同放射敏感性鼻咽癌细胞株中表达.癌症,2003,22(6)：579-581.
[46]Sang M, Li Y, Ozaki T,et al. p73-dependent induction of 14-3-3sigma increases the chemo-sensitivity of drug-resistant human breast cancers. Biochem Biophys Res Commun 2006;347:327-33.
[47]Marioni G, Koussis H, Gaio E,et al.MASPIN's prognostic role in patients with advanced head and neck carcinoma treated with primary chemotherapy (carboplatin plus vinorelbine) and radiotherapy:preliminary evidence.Acta Otolaryngol 2009; 129:786-92.
[48]Lee E, Nichols P, Spicer D,et al.GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer.Cancer Res 2006; 66:7849-53
[49]Suresh A,Tung F,Moreb J,et al. Role of manganese superoxide dismutase in radioprotection using gene transfer studies. Cancer Gene Ther 1994; 1:85-90.
[50]Hu S, Arellano M, Boontheung P, et al. Salivary Proteomics for Oral Cancer Biomarker Discovery.Clin Cancer Res 2008; 14:6246-52.
[51]Lee AW, Poon YF, Foo W, et al. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985:overall survival and patterns of failure.Int J Radiat Oncol Biol Phys 1992;23:261-70.
[52]Leung SF, Teo PM, Shiu WW, et al. Clinical features and management of distant metastases of nasopharyngeal carcinoma. J Otolaryngol 1991;20:27-9.
[53]Mhawech P.14-3-3 proteins--an update. Cell Res 2005;15:228-36.
[54]Laronga C,Yang HY,Neal C,Lee MH. Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates cell cycle progression. J Biol Chem 2000;275:23106-12.
[55]Yang HY, Wen YY, Chen CH, Lozano G,Lee MH.14-3-3 sigma positively regulates p53 and suppresses tumor growth.Mol Cell Biol 2003; 23:7096-107.
[56]Gudkov AV, Komarova EA.The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer 2003;3:117-29.
[57]Sang M, Li Y, Ozaki T,et al.p73-dependent induction of 14-3-3sigma increases the chemo-sensitivity of drug-resistant human breast cancers. Biochem Biophys Res Commun 2006;347:327-33.
[58]Cheng AL,Huang WG,Chen ZC,et al.Identification of novel nasopharyngeal carcinoma biomarkers by laser capture microdissection and proteomic analysis. Clin Cancer Res 2008; 14:435-45.
[59]Sager R, Sheng S, Pemberton P, et al. Maspin. A tumor suppressing serpin.Adv Exp Med Biol 1997;425:77-88.
[60]Sheng S.The promise and challenge toward the clinical application of maspin in cancer.Front Biosci 2004;9:2733-45.
[61]Schaefer JS, Zhang M. Targeting maspin in endothelial cells to induce cell apoptosis. Expert Opin Ther Targets 2006; 10:401-8.
[62]Mhawech-Fauceglia P, Dulguerov P, Beck A, et al.Value of ezrin,maspin and nm23-H1 protein expressions in predicting outcome of patients with head and neck squamous-cell carcinoma treated with radical radiotherapy. J Clin Pathol 2007;60:185-9.
[63]Sheng S. A role of novel serpin maspin in tumor progression:the divergence revealed through efforts to converge. J Cell Physiol 2006; 209:631-5.
[64]Lee AS. The glucose-regulated proteins:stress induction and clinical applications.Trends Biochem Sci 2001;26:504-10.
[65]Hendershot LM. The ER function BiP is a master regulator of ER function. MtSinai J Med 2004;71:289-97.
[66]Dong D, Dubeau L, Bading J, et al. Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors. Hum Gene Ther 2004; 15:553-61.
[67]Zhai L, Kita K, Wano C, Wu Y, Sugaya S, Suzuki N. Decreased cell survival and DNA repair capacity after UVC irradiation in association with down-regulation of GRP78/BiP in human RSa cells. Exp Cell Res 2005;305:244-52.
[68]Li J, Lee AS. Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 2006;6:45-54.
[69]顾永清.SOD及其在生物学中的应用[J].生物学通报,1993,28：8-11.
[70]Church SL,Grant JW, Ridnour LA,et al. Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells[J].Proc Natl Acad Sci USA,1993;90:3113-3117.
[71]Urano M,Kuroda M,Reynolds R,et al.Expression of manganese uperoxide dismutase reduces tumor control radiation dose:gene-radiotherapy[J].Cancer Res,1995;55:2490-2493.
[72]Safford SE, Oberley TD, Urano M, et al. Suppression of fibrosarcoma metastasis by elevated expression of manganese superoxide dismutase[J].Cancer Res,1994;54:4261-4265.
[73]Sun J, Chen Y, Li M, Ge Z. Role of antioxidant enzymes on ionizing radiation resistance. Free Radic Biol Med 1998;24:586-93.
[74]Rhee SG, Kim KH, Chae HZ,et al.Antioxidant defense mechanisms:a newthiol-specific antioxidant enzyme.Ann N Y Acad Sci 1994; 738:86-92.
[75]Epperly MW, Epstein CJ, Travis EL,et al.Decreased pulmonary radiation resistance of manganese superoxide dismutase (MnSOD)-deficient mice is corrected by human manganese superoxide dismutase-Plasmid/Liposome (SOD2-PL) intratracheal gene therapy. Radiat Res 2000; 154:365-74.
[76]Ozeki M, Tamae D, Hou DX, et al. Response of cyclin B1 to ionizing radiation:regulation by NF-kappaB and mitochondrial antioxidant enzyme MnSOD.Anticancer Res 2004;24:2657-63.
[77]Kalen AL,Sarsour EH,Venkataraman S,et al.Mn-superoxide dismutase overexpression enhances G2 accumulation and radioresistance in human oral squamous carcinoma cells. Antioxid Redox Signal 2006;8:1273-81
[1]Andreassen CN, Alsner J, Overgaard M. Prediction of normal tissue radiosensitivity from polymorphisms in candidate genes. Radiother Oncol, 2003,69(2):127-135.
[2]Baumann M, Holscher T, Begg AC. Towards genetic prediction of radiation responses:ESTRO's GENEPI project. Radiother Oncol,2003,69(2):121-125.
[3]Olive PL. DNA damage and repair in individual cells:applications of the comet assay in radiobiology. Int J Radiat Biol,1999,75:3952405.
[4]Peggy L Olive, Judit P Banath. The comet assay:a method to measure DNA damage in individual cells. NATURE PROTOCOLS,2006,1 (.1):23-29
[5]闫洁,杨伟志.“彗星”分析法及应用.中华放射肿瘤学杂志.2002,11：66-68.
[6]高远红,杨伟志,闫洁,袁智勇,刘新帆,徐国镇.“彗星”分析法检测人癌裸鼠移植瘤的放射敏感性.中华放射肿瘤学杂志,2004,13(1)：48-51.
[7]Schwartz JL, Mustafi R, Beckett MA, et al. Prediction of the radiation sensitivity of human squamous cell carcinoma cells using DNA filter elution. Radiat Res,1990,123(1):1-6.
[8]Nunez MI, Guerrero MR, Lopez E, et al. DNA damage and prediction of radiation response in lymphocytes and epidermal skin human cells. Int J Cancer, 1998,76(3):354-361.
[9]高黎,杨伟志,袁智勇,徐国镇,高远红,王冕荣.改良.“彗星”分析法检测鼻咽癌放射敏感性的初步研究.中华放射肿瘤学杂志,2004,13(1)：39-43
[10]张玉晶,闫洁,高远红,李艳春,杨伟志.中性彗星分析法检测肿瘤细胞的放射敏感性.中国肿瘤,2004,13(11)：731-734
[11]Ando N, Nakajima T, Masuda H, et al.Antimicrotubule effects of the novel anti-tumor benzoylphenylurea derivative HO-221. Carcer Chemother Pharmacol,1995,37:63
[12]Johnson RT, Rao PN.Mammalian cell fusion:induction of premature chromosome condensation in interphase nuclei.Nature,1970,226 (5247):717-722.
[13]Suzuki M, Kase Y.Correlation between cell death and induction of non-rejoining pcc breaks by carbon-ion beams.Adv Space Res,1998, 22:561-568.
[14]夏云飞,李满枝,黄冰,等.14株(亚株)人鼻咽癌细胞的放射生物特性.癌症,2001,20(7)：683 687.
[15]石慧英,孙懿,易红,冯雪萍,陈主初,肖志强.p53沉默对人鼻咽癌细胞株CNE2放射生物学特性的影响.国际病理科学与临床杂志,2008,28(2)：97-102
[16]王亚利,王西京,王中卫,金迎迎,李毅.放射抗拒性鼻咽癌细胞系的建立及差异表达基因.西安交通大学学报(医学版),2009,30(6)：741-745,748.
[17]冯雪萍,刘伟,肖志强,黄生鹏,李建玲,易红,张鹏飞,段朝军.近致死量照射CNE1后存活克隆生物学性状初步分析.中国耳鼻咽喉颅底外科杂志,2007,13(4)：245-249.
[18]冯雪萍,陈主初,肖志强,易红,李建玲,杨轶轩.放疗诱导鼻咽癌细胞株CNE1热休克蛋白高表达.中国耳鼻咽喉颅底外科杂志,2005,11(2)：81-84.
[19]Achary MP, Jaggernauth W, Gross E, et al. Cell lines from the same cervical carcinoma but with different radiosensitivities exhibit different cDNA microarray patterns of gene expression. Cytogenet Cell Genet,2000, 91(1-4):39-43.
[20]Hanna E, Shrieve DC, Ratanatharathorn V, et al. A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck. Cancer Res,2001,61(6):2376-2380.
[21]Pusztai L, Ayers M, Stec J, et al. Clinical application of cDNA microarrays in oncology. Oncologist,2003,8(3):252-258.
[22]Harima Y, Sawada S, Miyazaki Y, et al. Expression of Ku80 in cervical cancer correlates with response to radiotherapy and survival. Am J Clin Oncol,2003, 26 (4):e80-85.
[23]Hasan RK, Wulfkuhle JD, Liotta LA, et al. STUDENTJAMA.Molecular technologies for personalized cancer management[J]. JAMA,2004, 291(13):1644-1645.
[24]Mian S, Ball G, Hornbuckle J, et al. A prototype methodology combining surface-enhanced laser desorption/ionization protein chip technology and artificial neural network algorithms to predict the chemoresponsiveness of breast cancer cell lines exposed to Paclitaxel and Doxorubicin under in vitro conditions[J].Proteomics,2003,3(9):1725-1737.
[25]Hagen JB. The origins of bioinformatics. Nat Rev Genet,2000,1 (3):231-6.
[26]沈瑜,肖海洁.肿瘤放射增敏剂在肿瘤放射治疗中的应用[J].中华肿瘤杂志,1999,21(3)：233-234
[27]蔡芸,陈志龙,赵芳,等.硝基咪唑类抗肿瘤放射增敏剂研究进展[J].中国新药杂志,2003,12(4)：249-252
[28]孙晋瑞,冯光玲,国大亮.肿瘤放疗增敏剂---甘氨双唑钠[J].齐鲁药事,2004,23(1)：32-35
[29]周厚清,邢成,李伯南.肿瘤放射增敏剂及增敏机制研究进展[J].国外医学·肿瘤学分册,2001,28(6)：756-751
[30]Pauwels B,Korst AE,dePooter CM,etal.The radiosensitising effect of gemcitabine and the influence of the rescue agent amifostine in vitro [J].Eur J Cancer,2003,39 (6):838-846
[31]陈晓晶,金一尊.生物还原剂的作用机理研究概况[J].辐射研究与辐射工艺学报,2003,21(2)：83-87
[32]Craighead P S,Pearcey R,Stuart G.A phase Ⅰ/Ⅱ evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer[J].Int J Radiat Oncol BiolPhys,2000,48(3):791-795
[33]Kasid U,Dritschilo A.RAF antisense oligonuclectide as a tumor radiosensitizer[J].Oncogene,2003,22(37):5876-5884
[34]刘琳,王锦鸿.中药对放射治疗增敏作用的研究概况[J].南京中医药大学学报,1999,15(1)：63-64
[35]李勤,谢艳华,孙纪元,等.中药安迪注射剂对人食管癌细胞的放射增敏作用[J].中国药科大学学报,2003,34(4)：356-358
[36]Lu J,Shao H.Survey on natural radiosensitizing agents since 2000 [J].J Chin Phar Sci,2003,12 (3):160-163
[37]Cecchini S,Girouard MA, Huels L,et al.Single-strand-specific radiosensitization of DNA by bromodeoxyuridine [J].Radiat Res,2004,162 (6):604-615
[38]李莉.放射增敏剂研究概况[J].国外医学·放射医学核医学分册,2001,25(2)：87-89
[39]罗波,于世英,庄亮,等.AG825对乳腺癌细胞的辐射增敏作用.中国肿瘤临床,2008,35(19)：1131-1134.
[40]郑秀龙,金一尊,沈瑜,等.肿瘤治疗增敏药.上海：上海科学技术文献出版社,2002：1014.