人肝癌细胞BEL-7402非常规照射模式生物效应探讨
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摘要
目的探讨三维适形照射(3DCRT)模式和急速照射模式对人肝癌细胞株BEL-7402生物效应变化的影响,存活分数及生物学参数的改变情况;观察人肝癌细胞株BEL-7402与人肝细胞株QSG-7701放射敏感性差异,为临床选择合适的放疗时间-剂量分割模式提供理论依据。
方法6MV X线两组模式照射人肝癌细胞BEL-7402(包括0,1,2,3,5,7,9,10Gy共8个吸收剂量点,剂量率3Gy/min):(1)急速照射组,照射完成时间0-4min;(2)模拟三维适形照射组:照射完成时间:13-15min。成克隆分析法计算存活分数,多靶单击数学模型拟合曲线,求出SF2,D0,Dq等参数值;6MV X线单次5Gy照射体外培养的人肝癌细胞BEL-7402、人肝细胞QSG-7701 ,采用MTT比色法、流式细胞术测定受照后不同时间(照射后6、12、24、36 h)细胞的存活率、凋亡率、细胞周期。
结果人肝癌细胞BEL-7402模拟急速照射组和三维适形照射组D0、Dq、SF2值分别为1.78和1.69;1.45和1.54;0.625和0.654;人肝细胞QSG-7701照后24 h凋亡率最高(18%),而BEL-7402细胞照后12h凋亡率最高(32%),存活率最低(65%),两株细胞照后12 h凋亡率和存活率差异最大(P<0.01)。QSG-7701在照后24h、BEL-7402在照后12h,G2/M期比例显著增高(分别为23.03±4.00%和43.23±6.44%)。
结论1.三维适形照射模式下分次照射时间延长,生物效应下降;2.人肝癌细胞株BEL-7402及人肝细胞株QSG-7701在照后存在放射敏感性差异;3.缩短3DCRT每分次照射时间和分次照射的间隔时间(如12h)可能会提高临床肝癌放疗疗效。
Objective To investigate the changes of radiobiological effects of BEL-7402 cells irradiated by two irradiation protocols(3-Dimensional conformal radiation therapy and acute irradiation), and its changes of surviving fraction and radiobiological parameters; To observe the differences of radiosensitivity between human hepatocarcinoma cells BEL-7402 and hepatic cells QSG-7701, approach the possible theoretical evidence .
Methods BEL-7402 cells irradiated to total doses of 0Gy, 1Gy, 2Gy, 3Gy, 5Gy, 7Gy, 9Gy, 10Gy at a dose rate of 3Gy/min in two different delivery patterns. In modeling acute irradiation, the fraction-delivery-time was 0-4 min; while in modeling 3-Dimensional conformal radiation therapy (3DCRT), the fraction-delivery-time was lasted 13-15 min. The surviving fractions were determined by classical colony forming assay. The radiobiological parameters were calculated, and cell survival curves were plotted according to“the single-hit multi-target model”. The survivability, apoptosis and cell cycles of BEL-7402 and QSG-7701 cells, which cultured in vitro and irradiated by 6MV X-ray with a single dose of 5 Gy, were assessed by methyl thiazole tetrazolium (MTT) assay and flow cytometry ( FCM ) at different time after irradiation.
Results The value of D0, Dq, SF2 of BEL-7402 cell line in acute irradiation pattern and 3DCRT irradiation pattern were 1.69 and 1.78 , 1.45 and 1.54, 0.625 and 0.654. The number of apoptotic BEL-7402 cells reached a peak (32 %) and a lowest survival (65%) at the 12h after irradiation, while irradiated apoptotic QSG-7701 cells showed highest (18%) at the 24h. Radiation induced significant differences in apoptosis and survival between the two cell lines at 12h(P<0.01). Cell cycle accumulation at G2/M phase of QSG-7701 cell after 24h exposure to this dose, and of BEL-7402 cell after 12h (23.03±4.00%,43.23±6.44%).
Conclusion 1.The radiobiological effectiveness can be influenced by prolonged fraction-delivery-time for 3DCRT. 2. The two cell lines were distinct from each other in radiosensitivity after irradiation. 3. To shorten fractionation schedules may have a beneficial effect of radiotherapy of hepatoma.
方法6MV X线两组模式照射人肝癌细胞BEL-7402(包括0,1,2,3,5,7,9,10Gy共8个吸收剂量点,剂量率3Gy/min):(1)急速照射组,照射完成时间0-4min;(2)模拟三维适形照射组:照射完成时间:13-15min。成克隆分析法计算存活分数,多靶单击数学模型拟合曲线,求出SF2,D0,Dq等参数值;6MV X线单次5Gy照射体外培养的人肝癌细胞BEL-7402、人肝细胞QSG-7701 ,采用MTT比色法、流式细胞术测定受照后不同时间(照射后6、12、24、36 h)细胞的存活率、凋亡率、细胞周期。
结果人肝癌细胞BEL-7402模拟急速照射组和三维适形照射组D0、Dq、SF2值分别为1.78和1.69;1.45和1.54;0.625和0.654;人肝细胞QSG-7701照后24 h凋亡率最高(18%),而BEL-7402细胞照后12h凋亡率最高(32%),存活率最低(65%),两株细胞照后12 h凋亡率和存活率差异最大(P<0.01)。QSG-7701在照后24h、BEL-7402在照后12h,G2/M期比例显著增高(分别为23.03±4.00%和43.23±6.44%)。
结论1.三维适形照射模式下分次照射时间延长,生物效应下降;2.人肝癌细胞株BEL-7402及人肝细胞株QSG-7701在照后存在放射敏感性差异;3.缩短3DCRT每分次照射时间和分次照射的间隔时间(如12h)可能会提高临床肝癌放疗疗效。
Objective To investigate the changes of radiobiological effects of BEL-7402 cells irradiated by two irradiation protocols(3-Dimensional conformal radiation therapy and acute irradiation), and its changes of surviving fraction and radiobiological parameters; To observe the differences of radiosensitivity between human hepatocarcinoma cells BEL-7402 and hepatic cells QSG-7701, approach the possible theoretical evidence .
Methods BEL-7402 cells irradiated to total doses of 0Gy, 1Gy, 2Gy, 3Gy, 5Gy, 7Gy, 9Gy, 10Gy at a dose rate of 3Gy/min in two different delivery patterns. In modeling acute irradiation, the fraction-delivery-time was 0-4 min; while in modeling 3-Dimensional conformal radiation therapy (3DCRT), the fraction-delivery-time was lasted 13-15 min. The surviving fractions were determined by classical colony forming assay. The radiobiological parameters were calculated, and cell survival curves were plotted according to“the single-hit multi-target model”. The survivability, apoptosis and cell cycles of BEL-7402 and QSG-7701 cells, which cultured in vitro and irradiated by 6MV X-ray with a single dose of 5 Gy, were assessed by methyl thiazole tetrazolium (MTT) assay and flow cytometry ( FCM ) at different time after irradiation.
Results The value of D0, Dq, SF2 of BEL-7402 cell line in acute irradiation pattern and 3DCRT irradiation pattern were 1.69 and 1.78 , 1.45 and 1.54, 0.625 and 0.654. The number of apoptotic BEL-7402 cells reached a peak (32 %) and a lowest survival (65%) at the 12h after irradiation, while irradiated apoptotic QSG-7701 cells showed highest (18%) at the 24h. Radiation induced significant differences in apoptosis and survival between the two cell lines at 12h(P<0.01). Cell cycle accumulation at G2/M phase of QSG-7701 cell after 24h exposure to this dose, and of BEL-7402 cell after 12h (23.03±4.00%,43.23±6.44%).
Conclusion 1.The radiobiological effectiveness can be influenced by prolonged fraction-delivery-time for 3DCRT. 2. The two cell lines were distinct from each other in radiosensitivity after irradiation. 3. To shorten fractionation schedules may have a beneficial effect of radiotherapy of hepatoma.
引文
[1]曾昭冲.肝细胞癌的放射治疗[J].实用肿瘤杂志,2007,22(5):08.3-48.3
[2] Dawson LA, Normolle D, Balter JM, et aL. Analysis of radiation-induced liver disease using the Lyman NTCP model [J]. Int J Radiat Oncol Biol Phys,2002,53(4):810～821.
[3] Hawkins MA, Dawson LA. Radiation Therapy for Hepatocellular Carcinoma From Palliation to Cure [J]. CANCER 2006,106(8):1653-63.
[4] Zeng ZC, Fan J. A comparison of treatment combinations with and without radiotherapy for hepatocellular carcinoma with portal vein and /or inferior vena cava tumor thrombus [J]. Int J Radiation Oncology Boil Phys 2005,61(2): 432 - 443.
[5] Yamashita H, Nakagawa K, Shiraishi K, et al. Radiotherapy for lymph node metastases in patients with hepatocellular carcinoma:Retrospective study[J]. J Gastroenterol Hepatol 2007,22,(4):523-527.
[6] Verhey LI. Physical considerations in the use of intensity modulated radiotherapy to produce three-dimensional conformal dose distributions [J]. J Jpn Soc Ther Radiol Oncol 2000,12,191-203.
[7] Florian Sterzing, Marc W. Münter, et al. Radiobiological Investigation of Dose-Rate Effects in Intensity-Modulated Radiation Therapy. Strahlenther Onkol, 2005, 181(1): 42-48.
[8] Zeng ZC, Jiang GL. DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma Hep G2 cell line [J]. World J Gastroenterol, 2002, 8(5): 797-803.
[9] Fisher DR, Hendry JH. Dose fractionation and hepatocyte clonogens:alpha/beta congruent to 1-2Gy,and beta decreases with increasing delay before assay [J]. Radiat Res,1988,113(1):51～57.
[10] Seong J , Keum KC , Han KH , et al . Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma [J]. Int J Radiat Oncol Biol Phys 1999,43(2):393-397.
[11]叶胜龙、秦叔逵整理吴孟超、汤钊猷、孙燕、管忠震审阅.原发性肝癌规范化诊治的专家共识[J].肿瘤,2009,29(4):295-304.
[12]石卫民,范义湘,陈龙华等.两株人肝癌细胞QSG-7701和Hep G2放射敏感性的体外研究[J].癌症,2002,21(9):1020-1021.
[13] R.V. Tse, Chandan Guha, L.A. Dawson. Conformal radiotherapy for hepatocellular carcinoma [J]. Hematology 2008 (67):113–123
[14]蒋国梁.原发性肝癌治疗的新方法——三维适形放疗[J] .癌症进展杂志2006,4(4): 279-283.
[15] Zhou ZH, Liu LM, Chen WW, et al. Combined therapy of transcatheter arterial chemoembolisation and three-dimensional conformal radiotherapy for hepatocellular carcinoma [J]. Br J Radiol 2007,80 (951): 194-201.
[16]王志.调强放疗中剂量率改变对生物效应的影响[J].实用癌症杂志,2007,22(5):529-531,537.
[17]殷蔚伯,余子豪,徐国镇.肿瘤放射治疗学[M].第4版,北京:中国协和医科大学出版社,2008:480,149-182, 231-239,280-284, 292-306,101-112, 270-277.
[18] Evans JW, Liu XF, Kirchgessner CU, et al. Inductionand repair of chromosome aberrations in scid cells measured by premature chromosome condensation[J]. Radiat Res,1996,145(1):39-46.
[19] Zheng XK, Chen LH, Yan X, et al. Impact of prolonged fraction dose-delivery time modeling intensity-modulated radiation therapy on hepatocellular carcinoma cell killing[J].World J Gastroenterol,2005, 11 (10):1452-1456.
[20]刘树铮鞠桂芝李修义龚守良.医学放射生物学[M].第三版.北京:原子能出版社,2006.6
[21] Elkind MM, Sutton H. X-ray damage and recovery in mammalian cells in culture[J]. Nature,1959,184:1293-1295.
[22] Shibamoto, Y., Ito, M., Sugie,C., et al. Recovery from sublethal damage during intermittent exposures in cultured tumor cells: implications for dose modification in radiosurgery and IMRT[J]. Int. J. Radiat. Oncol. Biol. Phys.2004,59(5):1484-1490.
[23] Wang, H., Zeng, Z.C., Bui, T. A., et al. Nonhomologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA2[J]. Cancer Res,2001,61(1):270-277.
[24] Hiroyuki OGINO, Yuta SHIBAMOTO, Chikao SUGIE, et al. Biological effects of intermittent radiation in cultured tumor cells: influence of fraction number and dose per fraction [J]. J. Radiat. Res., 2005, 46(4):401-406.
[25] JIAN Z. WANG,X. ALLEN LI,WARREN D. D’SOUZA,et al. Impact Of Prolonged Fraction Delivery Times On Tumor Control: A Note Of Caution For Intensity-Modulated Radiation Therapy (IMRT)[J]. Int J Radiation Oncology Biol Phys,2003,57(2):543–552.
[26] Brenner DJ, Hall EJ. Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy [J]. Int J Radiat Oncal Biol Phys1991,20(1):181-190.
[27] Morgan WF, Naqvi SA, Yu C, et al. Does the time required to deliver IMRT reduce its biological effectiveness? [J]. Int J Radiat Oncol Biol Phys(abstr),2002,54:222.
[28] MuX, Loforth PO, Karlsson M, et al. The effect of fraction time in intensity modulated radiotherapy: theoretical and experimental evaluation of an optimization problem [J]. Radiother Oncol, 2003, 68(2): 181-187.
[29] Sachs RK, Hahnfeld P, Brenner DJ. The link between low-LET dose-response relations and the underlying kinetics of damage production/repair/misrepair[J].Int J Radiat Biol,1997,72(4):351-374.
[30] Paganetti H. Changes in tumor cell response due to prolonged dose delivery times in fractionated radiation therapy[J].Int J Radiation Oncology Biol Phys, 2005, 63(3): 892-900.
[31] Sugie C, Shibamoto Y, Ito M,et al. Radiobiologic effect of intermittent radiation exposure in murine tumors[J].Int J Radiat Oncol Biol Phys,2006,64(2):619-624.
[32] Fowler JF, Welsh JS, Howard SP. Loss of biological effect in prolonged fraction delivery[J].Int J Radiat Oncol Biol Phys,2004,59(1):242-249.
[33] Crooks SM, McAven LF, Robinson DF, et al. Minimizing delivery time and monitor unites in static IMRT by leafsequencing [J]. Phys Med Biol 2002,47(17):3105-3116
[34] Pow EH, Kwong DL, Mcmillan AS,et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomizedcontrolled clinical trial[J].Int J Radiat Oncol Biol Phys, 2006, 66(4): 981-991.
[35] Liu Y, Chen M, Zhao C,et al. Radiation-induced Temporomandibular Joint Damage in Nasopharyngeal Carcinoma Patients after Intensity -modulated Radiotherapy [J]. Chinese jounal of Cancer, 2007, 26 (1):64-66.
[36] Dunne AL , Price ME , Mothersill C , et al . Relationship between clonogenic radiosensitivity, radiation-induced apoptosis and DNA damage/ repair in human colon cancer cells [J]. Br J Cancer 2003,89 (12):2277-2283.
[37] Mitsubashi N, Takahashi H, SakuraiM,et al. A radioresistant variant cell line, NMT-1R,isolated from a radiosensitive rar yolk sac tumor cell line. NTM-1: differences of early, radiation-induced morphological changes, especially apoptosis[J]. Int J Radiation Oncology Biol Phys, 1996, 69 (2):329.
[38]冯文峰,黄理金,漆松涛,等.放射诱导大鼠脑神经元和胶质细胞凋亡及敏感性的比较研究[J].中华放射医学与防护杂志,2004,24(2):111.
[39] Stark JR,Taylor WR.Control of the G2/M transition[J]. Mol Biotechnol, 2006, 32(3):227-248.
[40]苏旭,金光辉,薛丽香,等.电离辐射对不同肿瘤细胞细胞周期的影响[J].中华放射医学与防护杂志,2000,20(3):168-170.
[41]夏景光,李文建,魏巍,等.3Gyγ射线对不同肿瘤细胞细胞周期进程的影响[J].核技术,2005,28(8):621-624.
[42]刘光伟,龚守良.电离辐射诱导的细胞G2期阻滞[M].国外医学:放射医学核医学分册,2002,26(4):180-182.
[43]王春刚肖作平.大分割三维适形放疗治疗不能手术原发性肝癌[J].中国癌症杂志2006,32(2):481-483.
[44]朱小东、梁世雄.原发性肝癌伴门静脉癌栓的大分割三维适形放疗效果分析[J].中华放射肿瘤学杂志,2005,14(6):476.
[1]Takahashi S.Conformation radiotherapy-rotation techniques as applied to radiography and radiotherapy for cancer [J].Acta Radiol,1965, 242(suppl):1-42.
[2]MaBjarngard BE, Kijewski PK, Pashby C. Description of a computer controlled chine [J]. Int J Radiat Oncol Biol Phys,1997(2):142.
[3]Nutting C, Dearnaley DP, Webb S. Intensity modulated radiation therapy: a clinical review [J]. The British Journal of Radiology, 2000(73):459-469.
[4]Bogner L, Scherer J, Treutwein M, et al. Verification of IMRT: techniques and problems [J]. Strahlenther Onkol 2004,180(6):340-350.
[5]余子豪.肿瘤放射治疗的发展和展望.广西医学,2005,27(6):771.
[6] Teh BS, Woo S, Butler EB. Intensity modulated radiation therapy (IMRT): a new promising technology in radiation oncology [J]. Oncologist, 1999, 4(6): 433-443.
[7] Bulter EB, Teh BS, Grant WH, et al. SMART boost: a new accelerated fractionation schedule for the treatment of head and neck cancer with intensity modulated radiotherapy [J]. Int J Radiat Oncol Biol Phys , 1999 ,45(1):21-32.
[8]刘卫东,王绪.调强放射治疗中的问题[J].中华放射医学与防护杂志,2004,24(6):590-593
[9]蒋国梁.三维适形放疗和调强放疗[J].肿瘤,2003,23(4):261-262.
[10]于金明,李宝生.调强放射治疗的临床应用现状与存在的问题[J].中华肿瘤杂志2005,27(3):188-190.
[11]Lee N, Xia P, Akazawa P ,et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma :An update of the UCSFexperience[J]. Int J Radiat Oncol Biol Phys,2002, 53(1):12-22.
[12] Uy NW, Woo SY, Teh BS, et al . Intensity-modulated radiation therapy (IMRT) for meningioma. Int J Radiat Oncol Biol Phys,2002, 53(5): 1265-1270.
[13]Khoo VS, Oldham M, Adams EJ, et al. Comparison of intensity- modulated tomotherapy with stereotactically guided conformal radiotherapy for brain tumors[J]. Int J Radiat Oncol Biol Phys,1999, 45(2): 415-425.
[14]Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients[J].Int J Radiat Oncol Biol Phys,2002,53(5): 1111-1116.
[15] Pollack A, Zagars GK, Smith LG, et al. Preliminary result of a randomized radiotherapy dose-escalation study comparing 70Gy with 78Gy for prostate cancer[J]. J Clin Oncol,2000,18(23): 3904-3911.
[16] Liu HH, Wang X, Dong L ,et al . Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer[J]. Int J Radiat Oncol Biol Phys,2004,58(4): 1268-1279.
[17] Grills IS, Yan D, Martinez AA, et al. Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer:a comparison of intensity-modulated radiation therapy (IMRT) , 3D conformal radiation, and elective nodal irradiation[J]. Int J Radiat Oncol Biol Phys ,2003,57(3):875-890.
[18] Dirkx ML, Heijmen BJ. Beam intensity modulation for penumbraenhancement and field length reduction in lung cancer treatment[J]. Radiother Oncol,2000,56(2):181-188.
[19] Wang SL,Liao Z,Liu H,et al.Intensity-modulated radiation therapy with concurrent chemotherapy for locally advanced cervical and upper thoracic esophageal cancer[J].World J Gastroenterol,2006,12(34):5501-5508.
[20]王军,韩春,李晓宁.食管癌调强放射治疗初期疗效分析[J].癌症,2009, 28(11):1138-1142
[21] Moody AM, Mayles WP, Bliss JM, et al. The influence of breast size on late radiation effects and association with radiotherapy dose in homogeneity[J]. Radiother Oncol,1994,33(2):106-112.
[22] Vicini FA, Sharpe M, Kestin L, et al. Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy[J]. Int J Radiat Oncol Bio Phys,2002,54(5):1336-1344.
[23] Hurkmans CW, Cho BC, et al. Reduction of cardiac and lung complication probabilities after breast irradiation using conformal radiotherapy with or without intensity modulation[J]. Radiother Oncol,2002,62(2):163-171.
[24] Remouchamps VW, Vicini FA , Sharpe MB , et al. Significant reductions in heart and lung doses using deep inspiration breath hold with active breathing control and intensity-modulated radiation therapy for patients treated with locoregional breast irradiation[J]. Int J Radiat Oncol Biol Phys,2003,55(2):392-406.
[25]Balter JM, Brock KK, Litzenberg DW, et al. Daily targeting of intrahepatic tumors for radiotherapy[J]. Int J Radiat Oncol Biol Phys,2002,52(1):266-271.
[26]Cheung PC, Sixel KE, Tirona R, et al. Reproducibility of lung tumor position and reduction of lung mass within the planning target volume using active breathing control(ABC)[J]. Int J Radiat Oncol Biol Phys,2003,57(5):1437-1442.
[27]杨伟志,冯宁远.近距离放射治疗的生物学.见:殷蔚伯,谷铣之,主编.肿瘤放射治疗学.第3版.北京:中国协和医科大学出版社,2002.321-322.
[28]Verhey LI. Physical considerations in the use of intensity modulated radiotherapy to produce three-dimensional conformal dose distributions [J]. J Jpn Soc Ther Radiol Oncol 2000, 12, 191-203
[29]钱立庭,杨伟志,刘新帆.模拟IMRT模式的生物效应研究初探[J].中华放射肿瘤学杂志,2005,14(5):431-433.
[30]Florian Sterzing, Marc W. Münter, et al. Radiobiological Investigation of Dose-Rate Effects in Intensity-Modulated Radiation Therapy. Strahlenther Onkol,2005,181(1):42-48.
[31]JIAN Z. WANG,X. ALLEN LI,WARREN D. D’SOUZA,et al. Impact Of Prolonged Fraction Delivery Times On Tumor Control: A Note Of Caution For Intensity-Modulated Radiation Therapy (IMRT)[J]. Int J Radiation Oncology Biol Phys,2003,57(2):543–552.
[32] Brenner DJ, Hall EJ. Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy [J]. Int J Radiat Oncal Biol Phys 1991,20(1):181-190.
[33] Morgan WF, Naqvi SA, Yu C, et al. Does the time required to deliver IMRT reduce its biological effectiveness? [J]. Int J Radiat Oncol BiolPhys(abstr),2002,54:222.
[34] MuX, Loforth PO, Karlsson M, et al. The effect of fraction time in intensity modulated radiotherapy: theoretical and experimental evaluation of an optimization problem [J]. Radiother Oncol, 2003, 68(2):181-187.
[35]刘树铮鞠桂芝李修义龚守良.医学放射生物学[M].第三版.北京:原子能出版社,2006.6.
[36]祝捷等,人鼻咽癌细胞CNE潜在性倍增时间(Tpot)与其放射后再增殖[J].中华放射肿瘤学杂志,1996,5(2):11-14.
[37]于金明,陈少卿.生物靶区与生物适形放疗研究进展[J].中华肿瘤杂志,2006,28(11):801-803.
[2] Dawson LA, Normolle D, Balter JM, et aL. Analysis of radiation-induced liver disease using the Lyman NTCP model [J]. Int J Radiat Oncol Biol Phys,2002,53(4):810～821.
[3] Hawkins MA, Dawson LA. Radiation Therapy for Hepatocellular Carcinoma From Palliation to Cure [J]. CANCER 2006,106(8):1653-63.
[4] Zeng ZC, Fan J. A comparison of treatment combinations with and without radiotherapy for hepatocellular carcinoma with portal vein and /or inferior vena cava tumor thrombus [J]. Int J Radiation Oncology Boil Phys 2005,61(2): 432 - 443.
[5] Yamashita H, Nakagawa K, Shiraishi K, et al. Radiotherapy for lymph node metastases in patients with hepatocellular carcinoma:Retrospective study[J]. J Gastroenterol Hepatol 2007,22,(4):523-527.
[6] Verhey LI. Physical considerations in the use of intensity modulated radiotherapy to produce three-dimensional conformal dose distributions [J]. J Jpn Soc Ther Radiol Oncol 2000,12,191-203.
[7] Florian Sterzing, Marc W. Münter, et al. Radiobiological Investigation of Dose-Rate Effects in Intensity-Modulated Radiation Therapy. Strahlenther Onkol, 2005, 181(1): 42-48.
[8] Zeng ZC, Jiang GL. DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma Hep G2 cell line [J]. World J Gastroenterol, 2002, 8(5): 797-803.
[9] Fisher DR, Hendry JH. Dose fractionation and hepatocyte clonogens:alpha/beta congruent to 1-2Gy,and beta decreases with increasing delay before assay [J]. Radiat Res,1988,113(1):51～57.
[10] Seong J , Keum KC , Han KH , et al . Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma [J]. Int J Radiat Oncol Biol Phys 1999,43(2):393-397.
[11]叶胜龙、秦叔逵整理吴孟超、汤钊猷、孙燕、管忠震审阅.原发性肝癌规范化诊治的专家共识[J].肿瘤,2009,29(4):295-304.
[12]石卫民,范义湘,陈龙华等.两株人肝癌细胞QSG-7701和Hep G2放射敏感性的体外研究[J].癌症,2002,21(9):1020-1021.
[13] R.V. Tse, Chandan Guha, L.A. Dawson. Conformal radiotherapy for hepatocellular carcinoma [J]. Hematology 2008 (67):113–123
[14]蒋国梁.原发性肝癌治疗的新方法——三维适形放疗[J] .癌症进展杂志2006,4(4): 279-283.
[15] Zhou ZH, Liu LM, Chen WW, et al. Combined therapy of transcatheter arterial chemoembolisation and three-dimensional conformal radiotherapy for hepatocellular carcinoma [J]. Br J Radiol 2007,80 (951): 194-201.
[16]王志.调强放疗中剂量率改变对生物效应的影响[J].实用癌症杂志,2007,22(5):529-531,537.
[17]殷蔚伯,余子豪,徐国镇.肿瘤放射治疗学[M].第4版,北京:中国协和医科大学出版社,2008:480,149-182, 231-239,280-284, 292-306,101-112, 270-277.
[18] Evans JW, Liu XF, Kirchgessner CU, et al. Inductionand repair of chromosome aberrations in scid cells measured by premature chromosome condensation[J]. Radiat Res,1996,145(1):39-46.
[19] Zheng XK, Chen LH, Yan X, et al. Impact of prolonged fraction dose-delivery time modeling intensity-modulated radiation therapy on hepatocellular carcinoma cell killing[J].World J Gastroenterol,2005, 11 (10):1452-1456.
[20]刘树铮鞠桂芝李修义龚守良.医学放射生物学[M].第三版.北京:原子能出版社,2006.6
[21] Elkind MM, Sutton H. X-ray damage and recovery in mammalian cells in culture[J]. Nature,1959,184:1293-1295.
[22] Shibamoto, Y., Ito, M., Sugie,C., et al. Recovery from sublethal damage during intermittent exposures in cultured tumor cells: implications for dose modification in radiosurgery and IMRT[J]. Int. J. Radiat. Oncol. Biol. Phys.2004,59(5):1484-1490.
[23] Wang, H., Zeng, Z.C., Bui, T. A., et al. Nonhomologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA2[J]. Cancer Res,2001,61(1):270-277.
[24] Hiroyuki OGINO, Yuta SHIBAMOTO, Chikao SUGIE, et al. Biological effects of intermittent radiation in cultured tumor cells: influence of fraction number and dose per fraction [J]. J. Radiat. Res., 2005, 46(4):401-406.
[25] JIAN Z. WANG,X. ALLEN LI,WARREN D. D’SOUZA,et al. Impact Of Prolonged Fraction Delivery Times On Tumor Control: A Note Of Caution For Intensity-Modulated Radiation Therapy (IMRT)[J]. Int J Radiation Oncology Biol Phys,2003,57(2):543–552.
[26] Brenner DJ, Hall EJ. Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy [J]. Int J Radiat Oncal Biol Phys1991,20(1):181-190.
[27] Morgan WF, Naqvi SA, Yu C, et al. Does the time required to deliver IMRT reduce its biological effectiveness? [J]. Int J Radiat Oncol Biol Phys(abstr),2002,54:222.
[28] MuX, Loforth PO, Karlsson M, et al. The effect of fraction time in intensity modulated radiotherapy: theoretical and experimental evaluation of an optimization problem [J]. Radiother Oncol, 2003, 68(2): 181-187.
[29] Sachs RK, Hahnfeld P, Brenner DJ. The link between low-LET dose-response relations and the underlying kinetics of damage production/repair/misrepair[J].Int J Radiat Biol,1997,72(4):351-374.
[30] Paganetti H. Changes in tumor cell response due to prolonged dose delivery times in fractionated radiation therapy[J].Int J Radiation Oncology Biol Phys, 2005, 63(3): 892-900.
[31] Sugie C, Shibamoto Y, Ito M,et al. Radiobiologic effect of intermittent radiation exposure in murine tumors[J].Int J Radiat Oncol Biol Phys,2006,64(2):619-624.
[32] Fowler JF, Welsh JS, Howard SP. Loss of biological effect in prolonged fraction delivery[J].Int J Radiat Oncol Biol Phys,2004,59(1):242-249.
[33] Crooks SM, McAven LF, Robinson DF, et al. Minimizing delivery time and monitor unites in static IMRT by leafsequencing [J]. Phys Med Biol 2002,47(17):3105-3116
[34] Pow EH, Kwong DL, Mcmillan AS,et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomizedcontrolled clinical trial[J].Int J Radiat Oncol Biol Phys, 2006, 66(4): 981-991.
[35] Liu Y, Chen M, Zhao C,et al. Radiation-induced Temporomandibular Joint Damage in Nasopharyngeal Carcinoma Patients after Intensity -modulated Radiotherapy [J]. Chinese jounal of Cancer, 2007, 26 (1):64-66.
[36] Dunne AL , Price ME , Mothersill C , et al . Relationship between clonogenic radiosensitivity, radiation-induced apoptosis and DNA damage/ repair in human colon cancer cells [J]. Br J Cancer 2003,89 (12):2277-2283.
[37] Mitsubashi N, Takahashi H, SakuraiM,et al. A radioresistant variant cell line, NMT-1R,isolated from a radiosensitive rar yolk sac tumor cell line. NTM-1: differences of early, radiation-induced morphological changes, especially apoptosis[J]. Int J Radiation Oncology Biol Phys, 1996, 69 (2):329.
[38]冯文峰,黄理金,漆松涛,等.放射诱导大鼠脑神经元和胶质细胞凋亡及敏感性的比较研究[J].中华放射医学与防护杂志,2004,24(2):111.
[39] Stark JR,Taylor WR.Control of the G2/M transition[J]. Mol Biotechnol, 2006, 32(3):227-248.
[40]苏旭,金光辉,薛丽香,等.电离辐射对不同肿瘤细胞细胞周期的影响[J].中华放射医学与防护杂志,2000,20(3):168-170.
[41]夏景光,李文建,魏巍,等.3Gyγ射线对不同肿瘤细胞细胞周期进程的影响[J].核技术,2005,28(8):621-624.
[42]刘光伟,龚守良.电离辐射诱导的细胞G2期阻滞[M].国外医学:放射医学核医学分册,2002,26(4):180-182.
[43]王春刚肖作平.大分割三维适形放疗治疗不能手术原发性肝癌[J].中国癌症杂志2006,32(2):481-483.
[44]朱小东、梁世雄.原发性肝癌伴门静脉癌栓的大分割三维适形放疗效果分析[J].中华放射肿瘤学杂志,2005,14(6):476.
[1]Takahashi S.Conformation radiotherapy-rotation techniques as applied to radiography and radiotherapy for cancer [J].Acta Radiol,1965, 242(suppl):1-42.
[2]MaBjarngard BE, Kijewski PK, Pashby C. Description of a computer controlled chine [J]. Int J Radiat Oncol Biol Phys,1997(2):142.
[3]Nutting C, Dearnaley DP, Webb S. Intensity modulated radiation therapy: a clinical review [J]. The British Journal of Radiology, 2000(73):459-469.
[4]Bogner L, Scherer J, Treutwein M, et al. Verification of IMRT: techniques and problems [J]. Strahlenther Onkol 2004,180(6):340-350.
[5]余子豪.肿瘤放射治疗的发展和展望.广西医学,2005,27(6):771.
[6] Teh BS, Woo S, Butler EB. Intensity modulated radiation therapy (IMRT): a new promising technology in radiation oncology [J]. Oncologist, 1999, 4(6): 433-443.
[7] Bulter EB, Teh BS, Grant WH, et al. SMART boost: a new accelerated fractionation schedule for the treatment of head and neck cancer with intensity modulated radiotherapy [J]. Int J Radiat Oncol Biol Phys , 1999 ,45(1):21-32.
[8]刘卫东,王绪.调强放射治疗中的问题[J].中华放射医学与防护杂志,2004,24(6):590-593
[9]蒋国梁.三维适形放疗和调强放疗[J].肿瘤,2003,23(4):261-262.
[10]于金明,李宝生.调强放射治疗的临床应用现状与存在的问题[J].中华肿瘤杂志2005,27(3):188-190.
[11]Lee N, Xia P, Akazawa P ,et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma :An update of the UCSFexperience[J]. Int J Radiat Oncol Biol Phys,2002, 53(1):12-22.
[12] Uy NW, Woo SY, Teh BS, et al . Intensity-modulated radiation therapy (IMRT) for meningioma. Int J Radiat Oncol Biol Phys,2002, 53(5): 1265-1270.
[13]Khoo VS, Oldham M, Adams EJ, et al. Comparison of intensity- modulated tomotherapy with stereotactically guided conformal radiotherapy for brain tumors[J]. Int J Radiat Oncol Biol Phys,1999, 45(2): 415-425.
[14]Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients[J].Int J Radiat Oncol Biol Phys,2002,53(5): 1111-1116.
[15] Pollack A, Zagars GK, Smith LG, et al. Preliminary result of a randomized radiotherapy dose-escalation study comparing 70Gy with 78Gy for prostate cancer[J]. J Clin Oncol,2000,18(23): 3904-3911.
[16] Liu HH, Wang X, Dong L ,et al . Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer[J]. Int J Radiat Oncol Biol Phys,2004,58(4): 1268-1279.
[17] Grills IS, Yan D, Martinez AA, et al. Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer:a comparison of intensity-modulated radiation therapy (IMRT) , 3D conformal radiation, and elective nodal irradiation[J]. Int J Radiat Oncol Biol Phys ,2003,57(3):875-890.
[18] Dirkx ML, Heijmen BJ. Beam intensity modulation for penumbraenhancement and field length reduction in lung cancer treatment[J]. Radiother Oncol,2000,56(2):181-188.
[19] Wang SL,Liao Z,Liu H,et al.Intensity-modulated radiation therapy with concurrent chemotherapy for locally advanced cervical and upper thoracic esophageal cancer[J].World J Gastroenterol,2006,12(34):5501-5508.
[20]王军,韩春,李晓宁.食管癌调强放射治疗初期疗效分析[J].癌症,2009, 28(11):1138-1142
[21] Moody AM, Mayles WP, Bliss JM, et al. The influence of breast size on late radiation effects and association with radiotherapy dose in homogeneity[J]. Radiother Oncol,1994,33(2):106-112.
[22] Vicini FA, Sharpe M, Kestin L, et al. Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy[J]. Int J Radiat Oncol Bio Phys,2002,54(5):1336-1344.
[23] Hurkmans CW, Cho BC, et al. Reduction of cardiac and lung complication probabilities after breast irradiation using conformal radiotherapy with or without intensity modulation[J]. Radiother Oncol,2002,62(2):163-171.
[24] Remouchamps VW, Vicini FA , Sharpe MB , et al. Significant reductions in heart and lung doses using deep inspiration breath hold with active breathing control and intensity-modulated radiation therapy for patients treated with locoregional breast irradiation[J]. Int J Radiat Oncol Biol Phys,2003,55(2):392-406.
[25]Balter JM, Brock KK, Litzenberg DW, et al. Daily targeting of intrahepatic tumors for radiotherapy[J]. Int J Radiat Oncol Biol Phys,2002,52(1):266-271.
[26]Cheung PC, Sixel KE, Tirona R, et al. Reproducibility of lung tumor position and reduction of lung mass within the planning target volume using active breathing control(ABC)[J]. Int J Radiat Oncol Biol Phys,2003,57(5):1437-1442.
[27]杨伟志,冯宁远.近距离放射治疗的生物学.见:殷蔚伯,谷铣之,主编.肿瘤放射治疗学.第3版.北京:中国协和医科大学出版社,2002.321-322.
[28]Verhey LI. Physical considerations in the use of intensity modulated radiotherapy to produce three-dimensional conformal dose distributions [J]. J Jpn Soc Ther Radiol Oncol 2000, 12, 191-203
[29]钱立庭,杨伟志,刘新帆.模拟IMRT模式的生物效应研究初探[J].中华放射肿瘤学杂志,2005,14(5):431-433.
[30]Florian Sterzing, Marc W. Münter, et al. Radiobiological Investigation of Dose-Rate Effects in Intensity-Modulated Radiation Therapy. Strahlenther Onkol,2005,181(1):42-48.
[31]JIAN Z. WANG,X. ALLEN LI,WARREN D. D’SOUZA,et al. Impact Of Prolonged Fraction Delivery Times On Tumor Control: A Note Of Caution For Intensity-Modulated Radiation Therapy (IMRT)[J]. Int J Radiation Oncology Biol Phys,2003,57(2):543–552.
[32] Brenner DJ, Hall EJ. Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy [J]. Int J Radiat Oncal Biol Phys 1991,20(1):181-190.
[33] Morgan WF, Naqvi SA, Yu C, et al. Does the time required to deliver IMRT reduce its biological effectiveness? [J]. Int J Radiat Oncol BiolPhys(abstr),2002,54:222.
[34] MuX, Loforth PO, Karlsson M, et al. The effect of fraction time in intensity modulated radiotherapy: theoretical and experimental evaluation of an optimization problem [J]. Radiother Oncol, 2003, 68(2):181-187.
[35]刘树铮鞠桂芝李修义龚守良.医学放射生物学[M].第三版.北京:原子能出版社,2006.6.
[36]祝捷等,人鼻咽癌细胞CNE潜在性倍增时间(Tpot)与其放射后再增殖[J].中华放射肿瘤学杂志,1996,5(2):11-14.
[37]于金明,陈少卿.生物靶区与生物适形放疗研究进展[J].中华肿瘤杂志,2006,28(11):801-803.