纳秒脉冲电场诱导肿瘤凋亡的窗口效应与实验研究
|
摘要
恶性肿瘤严重威胁人类生命健康,传统的治疗手段由于受其适应症、禁忌症和副作用等因素的限制,对恶性肿瘤的疗效仍不够理想。传统肿瘤治疗方法的机理在于杀伤肿瘤细胞并抑制其生长与增殖,因而只能延缓肿瘤的进展,不能达到治愈的目的。而诱导肿瘤细胞凋亡能使肿瘤组织缩小甚至消失,并减少对正常细胞的损害和治疗过程中的不良反应,因此,研究诱导肿瘤细胞凋亡的方法与机制,对于肿瘤治疗有着特别重要的意义。
为此,本文在传统电疗法的基础上,通过阐述各种参数脉冲电场的生物电效应共性基础理论,深入研究纳秒脉冲电场诱导肿瘤凋亡的方法和机制,取得的主要成果有:
①分别建立了球形细胞的多层介电模型、等效电路模型和场-路复合模型,提出了各种模型内外膜跨膜电位的计算方法,分析了内外膜跨膜电位对全时/频段(微秒-纳秒-皮秒)范围内脉冲电场的响应规律,从而提出了脉冲电场的脉宽-场强脉冲参数窗口效应和电导率-介电常数细胞电参数窗口效应。
②以传统脉冲功率技术中的电容充放电为基本原理,结合高压大功率电力电子开关及其触发技术、基于数字电位器和线性光耦的程控调压技术,研制出了一套高场强纳秒脉冲肿瘤治疗仪样机,该样机稳定可靠,并能对输出指数衰减纳秒脉冲的电压峰值(0～25kV)、脉冲宽度(100ns～1μs)、重复频率(1～100Hz)和脉冲个数等参数进行独立、精确控制。
③以离体人浆液囊腺性卵巢癌SKOV3肿瘤细胞为对象,采用场强10kV/cm、脉宽100ns的高场强纳秒脉冲电场进行处理,通过流式细胞术检测、扫描电子显微镜观察、透射电子显微镜观察、AO(吖啶橙)/EB(溴化乙啶)荧光检测、细胞内钙离子浓度检测等手段,证实了纳秒脉冲电场能有效诱导离体肿瘤细胞凋亡,其机制是通过激活细胞内钙库(内质网、线粒体),引起细胞内钙离子浓度升高,从而介导凋亡信号通路。
④以接种人黑色素瘤细胞A375的BALB/C裸鼠为对象,采用场强20kV/cm、脉宽300ns的高场强纳秒脉冲电场进行处理,通过抑瘤效应观察、透射电子显微镜观察、免疫荧光染色检测Caspase-3蛋白表达、RT-PCR检测Caspase-3 mRNA表达、TUNEL原位末端标记DNA降解等手段,证实了纳秒脉冲电场能有效诱导在体肿瘤凋亡并有效抑制其生长,其机制是通过激活肿瘤细胞Caspase-3蛋白酶而诱导肿瘤细胞调亡,从而使肿瘤组织缩小甚至消失。
综上所述,诱导肿瘤细胞凋亡是治疗肿瘤的最新研究热点和可能突破口,而纳秒脉冲电场能有效诱导肿瘤细胞凋亡并明显抑制在体肿瘤组织的生长,在局部肿瘤治疗领域显示出良好的应用前景。
Cancer is the main cause of people death. Traditional therapies are not satisfactory due to the limits of appropriateness, contraindication and side effects, etc. In fact, traditional therapies aim at killing caner cells or inhibiting tumor growth, patients can not heal in this way anyway. On the other hand, apoptosis induction could be another way to treat tumor because this way is very effective to make tumor shrink or disappear without any side effects. So, it is very important for tumor treatment to research method and mechanism of apoptosis induction.
Based on the traditional Electrical Therapy (ET), this paper analyzed the common basic bioelectrical mechanism of all kinds of Pulsed Electric Fields (PEF) and then proposed the detailed method and mechanism of Nanosecond Pulsed Electric Fields (nsPEF) for apoptosis induction. The main achievements in this paper are as follows:
①Three cell models, Multilayer Dielectric Model (MDM), Equivalent Circuit Model (ECM) and electric field - electric circuit compound model, were proposed firstly. Calculation methods for transmembrane potential of cell inner and outer membrane of these three models were performed while exposing cancer cells to Electric Field (EF). Based on the calculation results, Window Effects (WE) of duration - intensity - transmembrane potential, duration - intensity - biomedical effects and conductivity - dielectric constant - transmembrane potential were brought forward, and this supported theory basics for nsPEF to induce cancer cells apoptosis.
②A nsPEF generator sample was developed by technical combination of traditional Pulsed Power Technology (PPT), high power switcher technology and programmable voltage adjusting technology. This sample worked steadily and the parameters of its exponential decay output pulse, peak (0~25kV), duration (100ns~1μs) and repeat rate (1~100Hz), could be adjusted accurately. This supported hardware basics for nsPEF to induce cancer cells apoptosis.
③Medical cell experiment to investigate the apoptosis and changes of the intracellular calcium concentration ([Ca~(2+)]_i ) induced by nsPEF on human ovarian carcinoma cell line SKOV3 in vitro was carried on. SKOV3 cells were exposed to nsPEF (intensity of 10kV/cm, duration of 100ns, 1 Hz in 5 minutes). The results showed that early apoptotic rate of experimental group was significantly higher than that of the control group (P<0.01). The typical morphological features of apoptotic cells were observed by SEM and TEM. It was proved that nsPEF can mainly induced early apoptosis. The [Ca~(2+)]_i was markedly increased by treatment with nsPEF (P<0.01), while the increase showed no relationship to the extracellular calcium concentration (P>0.05). One of the mechanisms of the apoptosis is that nsPEF can activate intracellular calcium and result in increase of [Ca~(2+)]_i so as to induce apoptosis of SKOV3 cells.
④Medical animal experiment to research the apoptosis induction effects of nsPEF in vivo was performed. Tumor models in 20 female BALB/C nude mice were established by inoculating with human melanoma cells A375. These mice were randomly divided into treated group (exposed to exponential decay nsPEF with intensity of 20kV/cm, duration of 300ns and 1Hz in 5 minutes) and control group equally. 20 days later, compared with that of control group, tumor growth of treated group was effectively (P<0.01) inhibited, typical morphological apoptosis characteristics in ultrastructure were observed by TEM, expression of Caspase-3 and Caspase-3 mRNA were obviously increased using immunofluorescence and RT-PCR, respectively. These experiment results contributed evidence of tumor growth inhibition by nsPEF exposure in vivo. The mechanism was apoptosis induction effects of nsPEF on cancer cells by activating Caspase-3. This study presented the first in vivo evidence for apoptosis induction effects of nsPEF, and this supported possible tumor therapy utilizing nsPEF.
In summary, apoptosis induction is the research focus to treat cancer with great possibility. At the same time, nsPEF is effective to induce cancer cells apoptosis and inhibit tumor growth in vivo, which shows bright future for nsPEF to treat local tumor.
为此,本文在传统电疗法的基础上,通过阐述各种参数脉冲电场的生物电效应共性基础理论,深入研究纳秒脉冲电场诱导肿瘤凋亡的方法和机制,取得的主要成果有:
①分别建立了球形细胞的多层介电模型、等效电路模型和场-路复合模型,提出了各种模型内外膜跨膜电位的计算方法,分析了内外膜跨膜电位对全时/频段(微秒-纳秒-皮秒)范围内脉冲电场的响应规律,从而提出了脉冲电场的脉宽-场强脉冲参数窗口效应和电导率-介电常数细胞电参数窗口效应。
②以传统脉冲功率技术中的电容充放电为基本原理,结合高压大功率电力电子开关及其触发技术、基于数字电位器和线性光耦的程控调压技术,研制出了一套高场强纳秒脉冲肿瘤治疗仪样机,该样机稳定可靠,并能对输出指数衰减纳秒脉冲的电压峰值(0～25kV)、脉冲宽度(100ns～1μs)、重复频率(1～100Hz)和脉冲个数等参数进行独立、精确控制。
③以离体人浆液囊腺性卵巢癌SKOV3肿瘤细胞为对象,采用场强10kV/cm、脉宽100ns的高场强纳秒脉冲电场进行处理,通过流式细胞术检测、扫描电子显微镜观察、透射电子显微镜观察、AO(吖啶橙)/EB(溴化乙啶)荧光检测、细胞内钙离子浓度检测等手段,证实了纳秒脉冲电场能有效诱导离体肿瘤细胞凋亡,其机制是通过激活细胞内钙库(内质网、线粒体),引起细胞内钙离子浓度升高,从而介导凋亡信号通路。
④以接种人黑色素瘤细胞A375的BALB/C裸鼠为对象,采用场强20kV/cm、脉宽300ns的高场强纳秒脉冲电场进行处理,通过抑瘤效应观察、透射电子显微镜观察、免疫荧光染色检测Caspase-3蛋白表达、RT-PCR检测Caspase-3 mRNA表达、TUNEL原位末端标记DNA降解等手段,证实了纳秒脉冲电场能有效诱导在体肿瘤凋亡并有效抑制其生长,其机制是通过激活肿瘤细胞Caspase-3蛋白酶而诱导肿瘤细胞调亡,从而使肿瘤组织缩小甚至消失。
综上所述,诱导肿瘤细胞凋亡是治疗肿瘤的最新研究热点和可能突破口,而纳秒脉冲电场能有效诱导肿瘤细胞凋亡并明显抑制在体肿瘤组织的生长,在局部肿瘤治疗领域显示出良好的应用前景。
Cancer is the main cause of people death. Traditional therapies are not satisfactory due to the limits of appropriateness, contraindication and side effects, etc. In fact, traditional therapies aim at killing caner cells or inhibiting tumor growth, patients can not heal in this way anyway. On the other hand, apoptosis induction could be another way to treat tumor because this way is very effective to make tumor shrink or disappear without any side effects. So, it is very important for tumor treatment to research method and mechanism of apoptosis induction.
Based on the traditional Electrical Therapy (ET), this paper analyzed the common basic bioelectrical mechanism of all kinds of Pulsed Electric Fields (PEF) and then proposed the detailed method and mechanism of Nanosecond Pulsed Electric Fields (nsPEF) for apoptosis induction. The main achievements in this paper are as follows:
①Three cell models, Multilayer Dielectric Model (MDM), Equivalent Circuit Model (ECM) and electric field - electric circuit compound model, were proposed firstly. Calculation methods for transmembrane potential of cell inner and outer membrane of these three models were performed while exposing cancer cells to Electric Field (EF). Based on the calculation results, Window Effects (WE) of duration - intensity - transmembrane potential, duration - intensity - biomedical effects and conductivity - dielectric constant - transmembrane potential were brought forward, and this supported theory basics for nsPEF to induce cancer cells apoptosis.
②A nsPEF generator sample was developed by technical combination of traditional Pulsed Power Technology (PPT), high power switcher technology and programmable voltage adjusting technology. This sample worked steadily and the parameters of its exponential decay output pulse, peak (0~25kV), duration (100ns~1μs) and repeat rate (1~100Hz), could be adjusted accurately. This supported hardware basics for nsPEF to induce cancer cells apoptosis.
③Medical cell experiment to investigate the apoptosis and changes of the intracellular calcium concentration ([Ca~(2+)]_i ) induced by nsPEF on human ovarian carcinoma cell line SKOV3 in vitro was carried on. SKOV3 cells were exposed to nsPEF (intensity of 10kV/cm, duration of 100ns, 1 Hz in 5 minutes). The results showed that early apoptotic rate of experimental group was significantly higher than that of the control group (P<0.01). The typical morphological features of apoptotic cells were observed by SEM and TEM. It was proved that nsPEF can mainly induced early apoptosis. The [Ca~(2+)]_i was markedly increased by treatment with nsPEF (P<0.01), while the increase showed no relationship to the extracellular calcium concentration (P>0.05). One of the mechanisms of the apoptosis is that nsPEF can activate intracellular calcium and result in increase of [Ca~(2+)]_i so as to induce apoptosis of SKOV3 cells.
④Medical animal experiment to research the apoptosis induction effects of nsPEF in vivo was performed. Tumor models in 20 female BALB/C nude mice were established by inoculating with human melanoma cells A375. These mice were randomly divided into treated group (exposed to exponential decay nsPEF with intensity of 20kV/cm, duration of 300ns and 1Hz in 5 minutes) and control group equally. 20 days later, compared with that of control group, tumor growth of treated group was effectively (P<0.01) inhibited, typical morphological apoptosis characteristics in ultrastructure were observed by TEM, expression of Caspase-3 and Caspase-3 mRNA were obviously increased using immunofluorescence and RT-PCR, respectively. These experiment results contributed evidence of tumor growth inhibition by nsPEF exposure in vivo. The mechanism was apoptosis induction effects of nsPEF on cancer cells by activating Caspase-3. This study presented the first in vivo evidence for apoptosis induction effects of nsPEF, and this supported possible tumor therapy utilizing nsPEF.
In summary, apoptosis induction is the research focus to treat cancer with great possibility. At the same time, nsPEF is effective to induce cancer cells apoptosis and inhibit tumor growth in vivo, which shows bright future for nsPEF to treat local tumor.
引文
[1] C. D. Mathers, D. Loncar. Projections of global mortality and burden of disease from 2002 to 2030 [J]. Plos Medicine, 2006, 3(11): 2011-2029.
[2]乔志恒,范维铭.物理治疗学全书[M].北京:科学技术出版社. 2001.
[3]李力军.现代高新技术治疗恶性肿瘤[M].北京:人民军医出版社. 2003.
[4]张积仁,刘端祺.肿瘤物理治疗新技术[M].北京:人民军医出版社. 2005.
[5]谷铣之,刘泰福,潘国英.肿瘤放射治疗学[M].北京:人民卫生出版社. 1993.
[6]胥彬,许建华.抗癌药物与肿瘤化学治疗进展[M].北京:科学出版社. 2001.
[7]林世寅,李瑞英.现代肿瘤热疗学[M].北京:学苑出版社. 1997.
[8] H. Zhu, K. Zhou, L. Zhang, et al. High intensity focused ultrasound (HIFU) therapy for local treatment of hepatocellular carcinoma: Role of partial rib resection [J]. European Journal of Radiology, 2008, doi:10.1016/j.ejrad.2008.07.003.
[9]邹建中,伍烽,李佩希,廖翠蓉等.超声监控超声聚焦刀治疗肝癌及疗效评价研究[J].中国超声医学杂志, 2000, 16(10): 766-768.
[10]辛育龄.癌症的电化学治疗[M].北京:人民卫生出版社. 1995.
[11]李运泽.电化学治疗恶性肿瘤的研究进展[J].肿瘤研究与临床. 1998, 10(4): 280-282.
[12]宋之乙,辛育龄,李开华,殷瑞,等.直流电治疗恶性肿瘤的研究[J].中华实验外科杂志, 1991, 8(2): 63-64.
[13]辛育龄,权宽宏,宋久卿,等.电化学治疗恶性肿瘤的临床效果[J].中华肿瘤杂志, 1991, 13(6): 467-469.
[14]辛育龄,薛复舟,宋玉忱,等.电化学治疗中晚期肺癌的临床效果[J].中华胸心血管外科杂志, 1997, 13(3): 154-158.
[15]陈国权,徐万成,章五一,等.电化学治疗体表恶性肿瘤的临床疗效[J].癌症, 1994, 13(1): 64-65.
[16] J. C. Weaver. Electroporation of cells and tissues [J]. IEEE Transactions on Plasma Science, 2000, 28(1): 24-33.
[17] L. M. Mir and S. Orlwski. Mechanisms of electrochemotherapy [J]. Advanced Drug Delivery Reviews, 1999, 35: 107-118.
[18] L. M Mir. Electrochemotherapy polentiation of antitumor effect of bleomycin by electric pulses [J]. European Journal of Cancer, 1991, 27(1): 68-72.
[19] M. Belehraclek. Electrochemotherapy: a new antitumor treatment [J]. Cancer, 1993, 72(12): 3694-3700.
[20] E. Neumann and K. Rosenheck. Permeability changes included by electrical pulse in vesicular membranes [J]. Journal of Membrane Biology, 1972, 10: 279-290.
[21] U. Zimmermann, J. Vienken, G. Pilwat. Dielectric breakdown of cell membranes [J]. Biophysical Jourmal, 1974, 14(11): 881-899.
[22] K. J. Kinosita and T. Y. Tsong. Voltage includes formation and hemolysis of human erythocytes [J]. Biochimica et Biophysical Acta., 1979, 471: 227-242.
[23] T. Y. Tsong. Electroporation of cell membranes [J]. Biophysical Journal, 1991, 60: 297-306.
[24] M. Okino. Optimal electric condictions in electrical impulse chemotherapy [J]. Japanese Journal of Cancer Research, 1992, 83(10): 1095-1101.
[25] W. R. Panje, M. P. Hier, G. R. Garman, et al. Electroporation therapy of head and neck cancer [J]. Ann. Otol. Rhinol. Laryngol., 1998, 107: 779-785.
[26] D. Rabussay and S. Kornhauser. Frequently asked questions about electroporation therapy [J]. American Journal of Electromedicine, April 1998: 64-68.
[27] A. J. H. Sale and W. A. Hamilton. Effects of electric fields on microorganizms I killing of bacteria and yeasts [J]. Biochimica et Biophysical Acta., 1967, 118: 781-788.
[28] L. M. Mir, L. F. Glass, G. Ser?a, et al. Effective treatment of cutaneous and subcutaneous malignant tumors by electrochemotherapy [J]. British Journal of Cancer, 1998, 77(12): 2336-2342.
[29] M. Cemazar, D. Miklavcic, L. M. Mir, et al. Electrochemotherapy of tumours resistant to cisplatin: a study in a murine tumour model [J]. European Journal of Cancer, 2001, (37): 1166-1172.
[30] D. ?emrov, and D. Miklav?i?. Calculation of the electrical parameters in electrochemotherapy of solid tumours in mice [J]. Computers in Biology and Medicine, 1998, (28): 439-448.
[31] D. Miklav?i?, D. ?emrov, H. Mekid, et al. A validated model of in vivo electric field distribution in tissues for electrochemotherapy and for DNA electrotranfer for gene therapy [J]. Biochimica et Biophysica Acta., 2000, (1523): 73-83.
[32] T. Kotnik, L. M. Mir, K. Flisar, et al. Cell membrane electropermeabilization by symmetrical bipolar rectangular pulses [J]. Bioelectrochemistry, 2001, 54: 83-90.
[33] D. Miklavcic, D. Semrov, H. Mekid, et al. In vivo electroporation threshold determination [C]. Proceedings of the 22nd annual EMBS International Conference. 2000: 2815-2818.
[34] S. Rodríguez-Cuevas, S. Barroso-Bravo, J. Almanza-Estrada, et al. Electrochemotherapy in primary and metastatic skin tumors [J]: Phase trial using intralesional bleomycin, 2001, 32: 273-276.
[35] M. Marty, G. Sersa, J. R. Garbay, et al. Electrochemotherapy– An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study [J]. European Journal of Cancer (SUPPLEMENTS), 2006, 4: 3-13.
[36] J. R. Garbay, V. Billard, C. Bernat, et al. Successful repetitive treatments by electrochemotherapy of multiple unresectable Kaposi sarcoma nodules [J]. European Journal of Cancer (SUPPLEMENTS), 2006, 4: 29-31.
[37] G. A. Hofmann, S. B. Dev, S. Dimmer, et al. Electroporation therapy: A new approach for the treatment of head and neck cancer [J]. IEEE Transactions on Biomedical Engineering, 1999, 46(6): 752-759.
[38] G. A. Hofmann, and G. Evans. Electronic genetic-physical and biological aspects of cellular electromanipulation [J]. IEEE Engineering of Medical Biology, 1986, 5(4): 6-25.
[39] S. B. Dev, and G. A. Hofmann. Electrochemotherapy– A novel method of cancer treatment [J]. Cancer Treatment Reviews, 1994, 20: 105-115.
[40] R. Heller, R. Gilbert, and M. J. Jaroszeski. Clinical applications of electrochemotherapy [J]. Advanced Drug Delivery Reviews, 1999, 35(1): 119-129.
[41] M. J. Jaroszeski, D. Coppoda, G. Nesmith, et al. Effects of electrochemotherapy with bleomycin on normal liver tissue in a rat model [J]. European Journal of Cancer, 2001, 37: 414-421.
[42] M. J. Jaroszeski, D. Coppoda, C. Pottinger, et al. Treatment of hepatocellular carcinoma in a rat model using electrochemotherapy [J]. European Journal of Cancer, 2001, 37: 422-430.
[43]包家立,胡巧红,梁文权.电穿孔能量对药物经皮渗透速率的影响[J].仪器仪表学报, 2000, 21(5): 546-550.
[44]包家立,梁文权,胡巧红,高建青.经皮给药电穿孔技术的新进展[J].国外医学生物医学工程分册, 1998, 21(4): 222-228.
[45]包家立,梁文权,胡巧红,高建青.经皮给药电穿孔仪的研制[J].仪器仪表学报, 2000, 21(1): 66-69, 77.
[46]高建青,梁文权.促进药物经皮渗透的新方法——电穿孔技术[J].国外医学药学分册, 1997. 24(1): 42-45.
[47]刘长军,王保义,张弘,等.低强度快速电磁脉冲导致细胞电穿孔的研究[J].科学通报, 1999, 44(11): 1157-1161.
[48]汪和睦,汪洲.细胞电穿孔与电融合的机理及应用[J].生物化学与生物物理进展, 1994, 2(14): 322-326.
[49] J. C. Weaver. Electroporation: A dramatic, nonthermal electric field phenomenon [C]. InProceedings of the First World Congress for Electricity and Magnetism in Biology and Medicine. Lake Buena Vista, Florida. Academic Press. 1992.
[50] Y. A. Chizmadzhev. Electric breakdown of bilayer lipid membranes. II. Calculation of the transmembrane lifetime in the steady-state diffusion approximations [J]. Bioelectrochemistry and Bioenergetics, 1979, 6: 53-62.
[51] R. C. Lee. Electrical injury mechanisms: Electrical breakdown of cell membranes [J]. Plast. Reconstr. Surg., 1987, 80: 672-679.
[52] E. Neumann, A. E. Sowers and C. A. Jordan. Electroporation and electrofusion in cell biology [M]. New York. Plenum. 1989.
[53] L. H. Ramirez. Electrochemotherapy on liver tumors in rabbits [J]. British Journal of Cancer, 1998, 77(12): 2104-2111.
[54] G. Sersa. Tumor blood flow change induced by application of electrical pulses [J]. European Journal of Cancer, 1999, 35(4): 672-677.
[55]姚陈果.可控陡脉冲对恶性肿瘤细胞不可逆性电击穿的实验和机理研究[D].博士学位论文.重庆:重庆大学. 2003.6
[56]熊兰.陡脉冲抗肿瘤效应的实验研究和机理分析[D].博士学位论文.重庆:重庆大学. 2004.10.
[57] B. Rubinsky, G. Onik, and P. Mikus. Irreversible electroporation: A new ablation modality - clinical implications [J]. Technology in Cancer Research and Treatment, 2007, 6(1): 37-48.
[58] B. Rubinsky. Irreversible electroporation in medicine [J]. Technology in Cancer Research and Treatment, 2007, 6(4): 255-259.
[59] A. T. Esser, K. C. Smith, T. R. Gowrishankar. Towards solid tumor treatment by irreversible electroporation: Intrinsic redistribution of fields and currents in tissue [J]. Technology in Cancer Research and Treatment, 2007, 6(4): 261-273.
[60] J. F. Edd, R. V. Davalos. Mathematical modeling of irreversible electroporation for treatment planning [J]. Technology in Cancer Research and Treatment, 2007, 6(4): 275-286.
[61] E. Maor, A. Ivorra, J. Leor, B. Rubinsky. The effect of irreversible electroporation on blood vessels [J]. Technology in Cancer Research and Treatment, 2007, 6(4): 307-312.
[62] A. Ivorra, B. Rubinsky. In vivo electrical impedance measurements during and after electroporation of rat liver [J]. Bioelectrochemistry, 2007, 70: 287-295.
[63] A. Ivorra, B. Rubinsky. Electric field modulation in tissue electroporation with electrolytic and non-electrolytic additives [J]. Bioelectrochemistry, 2007, 70: 551-560.
[64] J. F. Edd, L. Horowitz, R. V. Davalos, et al. In vivo results of a new focal tissue ablation technique: Irreversible electroporation [J]. IEEE Transactions on Biomedical Engineering,2006, 53(5): 1409-1415.
[65] R. V. Davalos, L. M. Mir, and B. Rubinsky. Tissue ablation with irreversible electroporation [J]. Annals of Biomedical Engineering, 2005, 33(2): 223-231.
[66] L. Miller, J. Leor, and B. Rubinsky. Cancer cells ablation with irreversible electroporation [J]. Technology in Cancer Research and Treatment, 2005, 4(6): 1-7.
[67] K. H. Schoenbach, S. Xiao, R. P. Joshi, et al. The effect of intense subnanosecond electrical pulses on biological cells [J]. IEEE Transactions on Plasma Science, 2008, 36(2): 414-422.
[68] K. H. Schoenbach, B. Hargrave, R. P. Joshi, et al. Bioelectric effects of intense nanosecond pulses [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2007, 14(5): 1088-1109.
[69] S. J. Beebe, P. M. Fox, L. J. Rec, et al. Nanosecond pulsed electric field (nsPEF) effects on cells and tissues: apoptosis induction and tumor growth inhibition [J]. IEEE Transactions on Plasma Science, 2002, 30(1): 286-292.
[70] K. H. Schoenbach, F. E. Peterkin, R. W. Alden, et al. The effect of pulsed electric fields on biological cells: Experiments and applications [J]. IEEE Transactions on Plasma Science, 1997, 25(2): 284-292.
[71] K. H. Schoenbach, A. A. Ghazala, T. Vithoulkas, et al. The effect of pulsed electrical fields on biological cells [J]. IEEE in press, 1997: 73-78.
[72] K. H. Schoenbach, S. Katsuki, R. H. Stark, et al. Bioelectrics—new applications for pulsed power technology [J]. IEEE Transactions on Plasma Science, 2002, 30(1): 293-300.
[73] K. H. Schoenbach, S. J. Beebe, E. S. Buescher, et al. Intracell effect of ultrashort electrical pulses [J]. Bioelectromagnetics, 2001, 22(6): 440-448.
[74] E. S. Buescher, K. H. Schoenbach. Effects of submicrosecond, high intensity pulsed electric fields on living cells-intracellular electromanipulation [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2003, 10(5): 788-794.
[75] A. G. Pakhomov, A. Phinney, J. Ashmore, et al. Characterization of the cytotoxic effect of high-intensity, 10-ns duration electrical pulses [J]. IEEE Transactions on Plasma Science, 2004, 32(4): 1579-1586.
[76] M. Gundersen. Ultrashort pulse electroporation- applications of high pulsed electric fields to induced caspase activation of human lymphocytes [J]. IEEE Transactions on Plasma Science, 2000, 28(2): 667-670.
[77] N. Chen, K. H. Schoenbach, J. F. Kolb, et al. Leukemic cell intracellular responses to nanosecond electric fields [J]. Biochemical and Biophysical Research Communications, 2004, 317: 421-427.
[78] K. H. Schoenbach, R. P. Joshi, J. F. Kolb, et al. Ultrashort electrical pulses open a new gateway into biological cells [J]. Proceedings of the IEEE, 2004, 92(7): 1122-1137.
[79] E. S. Buescher, R. R. Smith, and K. H. Schoenbach. Submicrosecond intense pulsed electric field effects on intracellular free calcium: Mechanisms and effects [J]. IEEE Transactions on Plasma Science, 2004, 32(4): 1563-1572.
[80] P. T. Vernier, Y. H. Sun, L. Marcu, et al. Calcium bursts induced by nanosecond electric pulses [J]. Biochemical and Biophysical Research Communications, 2003, 310: 286-295.
[81] P. T. Vernier, M. S. Thu, L. Marcu, et al. Nanosecond electroperturbation—mammalian cell sensitivity and bacterial spore resistance [J]. IEEE Transactions on Plasma Science, 2004, 32(4): 1620-1625.
[82] M. Stacey, J. Stickley, P. Foxa, et al. Differential effects in cells exposed to ultra-short, high intensity electric fields: cell survival, DNA damage, and cell cycle analysis [J]. Mutation Research, 2003, 542: 65-75.
[83] R. P. Joshi, Q. Hu, K. H. Schoenbach, et al. Simulations of electroporation dynamics and shape deformations in biological cells subjected to high voltage pulses [J]. IEEE Transactions on Plasma Science, 2002, 30(4): 1536-1546.
[84] R. P. Joshi, Q. Hu, K. H. Schoenbach. Dynamical modeling of cellular response to short-duration, high-intensity electric fields [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2003, 10(5): 778-787.
[85] R. P. Joshi, Q. Hu, R. Aly, et al. Self-consistent simulations of electroporation dynamics in biological cells subjected to ultrashort electrical pulses [J]. Physical Review, 2001, 64, 011913.
[86] R. P. Joshi, Q. Hu, K. H. Schoenbach. Modeling studies of cell response to ultrashort, high-intensity electric fields—implications for intracellular manipulation [J]. IEEE Transactions on Plasma Science, 2004, 32(4): 1677-1686.
[87] J. F. R. Kerr, A. H. Wyllie, and A. R. Currie. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics [J]. British Journal of Cancer, 1972, 26: 239-257.
[88]彭黎明,王曾礼.细胞凋亡的基础与临床[M].北京:人民卫生出版社. 2000.
[89]胡野,凌志强,单小云.细胞凋亡的分子医学[M].北京:军事医学科学出版社. 2002.
[90]肖华娟,严萍,张适昌.纳秒脉冲细胞内电处理机理及其研究进展[J].高电压技术, 2004, 30(4): 39-41, 72.
[91] T. Kotnik, D. Miklavcic, T. Slivnik. Time course of transmembrane voltage induced by time-varying electric fields—a method for theoretical analysis and its application [J]. Bioelectrochemistry and Bioenergetics, 1998, 45: 3-16.
[92] L. M. Mir, S. Orlowski, J. Belehradek, et al. Biomedical applications of electric pulses with special emphasis on antitumor electrochemotherapy [J]. Bioelectrochemistry and Bioenergetics, 1995, 38: 203-207.
[93] G. Sersa, B. Stabuc, M. Cemazar, et al. Electrochemotherapy with cisplatin: Clinical experience in malignant melanoma patients [J]. Clinical Cancer Research, 2000, 6: 863-867.
[94] D. Miklavcic, K. Beravs, D. Semrov, et al. The importance of electric field distribution for effective in vivo electroporation of tissues [J]. Biophysical Journal, 1998, 74: 2152-2158.
[95] T. Kotnik, D. Miklavcic. Analytical description of transmembrane voltage induced by electric fields on spheroidal cells [J]. Biophysical Journal, 2000, 79: 670-679.
[96] K. Cheng. A biomechanical model of electroporation of a biological membrane [J]. IEEE in press, 1997: 70-73.
[97] K. Cheng. An improved biophysical model of electroporation of cell membrane [C]. Proceedings of the 18th annual EMBS International Conference, 1996: 1915-1916.
[98] K. Cheng. Development of biomechanical models of electroporation [J]. IEEE in press, 1995: 183-184.
[99]冯慈璋.电磁场[M].北京:高等教育出版社. 1994.
[100]邱关源.电路(第四版) [M].北京:高等教育出版社. 1999.
[101] A. L. Hodgkin, and A. F. Huxley. A quantitative description of ion currents and its applications to conduction and excitation in nerve membranes [J]. Journal of Physiology, 1952, 117: 500-544.
[102] H. Kanai, K. Sakamoto, M. Haeno, et al. Electrical measurement of fluid distribution in human legs: Estimation of extra- and intra-cellular fluid volume [J]. Journal of Microwave Power, 1983, 18(3): 235-248.
[103] K. R. Foster. Thermal and nonthermal mechanism of interaction of radio-frequency energy with biological systems [J]. IEEE Transactions on Plasma Science, 2000, 28(1): 15-23.
[104] I. Ermolina, Y. Polevaya, Y. Feldman, et al. Study of normal and malignant white blood cells by time domain dielectric spectroscopy [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2001, 8(2): 253-261.
[105] Y. Feldman, I. Ermolina, Y. Hayashi. Time domain dielectric spectroscopy study of biological systems [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2003, 10(5): 728-753.
[106]王莹.高功率脉冲电源[M].北京:原子能出版社. 1991.
[107]曾正中.实用脉冲功率技术引论[M].西安:陕西科学技术出版社. 2003.
[108]刘锡三.高功率脉冲技术[M].北京:国防工业出版社. 2005.
[109]周璧华,陈彬,石立华.电磁脉冲及其工程防护[M].北京:国防工业出版社. 2003.
[110]杨绍洲,廖伟光.加速器中闸流管的原理和维护[J].医疗设备信息, 2004, 19(7): 73-74.
[111]詹伟国.浅谈加速器中的氢闸流管[J].医疗装备, 2003, 12:47-48.
[112]李序宝,赵永健.电力电子器件及其应用[M].北京:机械工业出版社. 1996.
[113]沙占友.数字电位器设计原理与应用[M].北京:机械工业出版社. 2007.
[114]李树靖,林凌,李刚.线性光耦合器LOC110的原理与应用[J].世界电子元器件. 2002, 12: 44-46.
[115]潘耀谦,高丰,成军.细胞凋亡与细胞坏死比较的研究进展[J].动物医学进展, 2000, 21(4): 5-8.
[116] M. O. Hengartner. The biochemistry of apoptosis [J]. Nature, 2000, 407(6805): 770-776.
[117] A. G. Letai. Diagnosing and exploiting cancer's addiction to blocks in apoptosis [J]. Nature Reviews Cancer, 2008, 8: 121-132.
[118] M. S. Runge, and W, C, Patterson. Principles of molecular medicine (second edition) [M]. Totowa: Humana Press, 2006.
[119] F. L. Kiechle, and X. B. Zhang. Apoptosis: Biochemical aspects and clinical implications [J]. Clinica Chimica Acta, 2002, 326: 27-45.
[120] C. Twomey and J. V. McCarthy. Pathways of apoptosis and importance in development [J]. Journal of Cellular and Molecular Medicine, 2005, 9(2): 345-359.
[121] R. J. Bold, P. M. Termuhlen, and D. J. McConkey. Apoptosis, cancer and cancer therapy [J]. Surgical Oncology, 1997, 6: 133-142.
[122]张丽杰,赵振军.细胞凋亡与肿瘤发生及治疗新策略[J].临床荟萃, 2003, 18(7): 416-417.
[123] D. V. Krysko, T. V Berghe, K. D’Herde, et al. Apoptosis and necrosis: Detection, discrimination and phagocytosis [J]. Methods, 2008, 44(3): 205-221.
[124]辛华.细胞生物学实验[M].北京:科学出版社. 2001.
[125] N. Kaise, I. S. Edelman. Calcium dependence of glueocorticoid - induced lymphocytolysis [J]. Proceedings of the National Academy of Sciences of the United States of America, 1977, 74: 638-642.
[126] J. Krebs. The role of calcium in apoptosis [J]. BioMetals, 1998, 11: 375-382.
[127]郭静,蒲咏梅,张东才.钙离子信号与细胞凋亡[J].生物物理学报, 2005, 21(1): 1-18.
[128]张帅,崔隽,沈萍萍.细胞凋亡中的钙离子调控[J].细胞生物学杂志, 2007, 29: 785-790.
[129] L. Li, Y. C. Tian, M. O. Tadé, et al. Apoptosis of tumor cells by temperature and anti-tumor drug: microscopic and macroscopic investigations [J]. Journal of Thermal Biology, 2003, 28:321-329.
[130] Y. W. Liu, C. X. Wang, C. Y. Zheng, et al. Microcalorimetric study of the metabolism of U-937 cells undergoing apoptosis induced by the combined treatment of hyperthermia and chemotherapy [J]. Journal of Thermal Biology, 2002, 27: 129-135.
[131]邹丽娟,陈亚敏,徐晓颖,等.温热顺铂对肝癌细胞的杀伤效应及其诱导凋亡的研究[J].肿瘤防治研究, 2002, 29(1): 12-14.
[132] T. Sakurai, K. Itoh, Y. Liu, et al. Low temperature protects mammalian cells from apoptosis initiated by various stimuli in vitro [J]. Experimental Cell Research, 2005, 309: 264-272.
[133]高凌云,张洪,许国英,等.不同脑温对全脑缺血再灌注后相关基因及细胞凋亡的影响[J].福建医科大学学报, 2001, 35(2): 104, 108.
[134] A. K. Zaidi, R. S. Bagewadikar, M. Subramanian, et al. Effect of whole body hyperthermia (39℃, 1h) on radiation-induced apoptosis in Swiss mice [J]. Journal of Thermal Biology, 2004, 29: 3-8.
[135] A. Dieing, O. Ahlers, T. Kerner, et al. Whole body hyperthermia induces apoptosis in subpopulations of blood lymphocytes [J]. Immunobiology, 2003, 207: 265-273.
[136]刘晓翌,刘建军. Caspase与细胞凋亡[J].武汉大学学报(医学版), 2004, 25(6): 742-745.
[137]袁长青,丁振华. Caspase的活化及其在细胞凋亡中的作用[J].生理科学进展, 2002, 33(3): 220-224.
[138] Chen M, Wang J. Initiator caspases in apoptosis signaling pathways [J]. Apoptosis, 2002, 7(4): 313-319.
[139]李小明,孙志贤.细胞凋亡中的关键蛋白酶-Caspase-3 [J].国外医学分子生物学分册, 1999, 21(1): 6-9.
[140]戴锅生.传热学[M].北京:高等教育出版社. 1999.
[141] H. H. Pennes. Analysis of tissue and arterial blood temperatures in the resting forearm [J]. Journal of Applied Physiology, 1948, 1: 93-122.
[142] J. C.切托.生物传热学[M].北京:科学出版社. 1991.
[143]王存诚,陈槐卿.生物医学中的热物理探索[M].北京:科学出版社. 1994.
[144] R. V. Davalos, B. Rubinsky, and L. M. Mir. Theoretical analysis of the thermal effects during in vivo tissue electroporation [J]. Bioelectrochemistry, 2003, 61: 99-107.
[145] S. Tungjitkusolmun, S. T. Staelin, D. Haemmerich, et al. Three-dimensional finite-element analyses for radio-frequency hepatic tumor ablation [J]. IEEE Transactions on Biomedical Engineering, 2002, 49: 3-9.
[146]李辑熙,牛中奇.生物电磁学概论[M].西安:西安电子科技大学出版社. 1990.
[147]李和杰,张学学,伊耀繁.体表常热流法无损检测血液灌注率实验研究[J].中国生物医学工程学报, 2003, 22(5):393-398.
[148]杨昆,刘伟,朱光明.生物组织血液灌注率的无损测量研究[J].工程热物理学报, 2003, 24(1): 69-72.
[149]陈品健.动物生物学[M],北京:科学出版社. 2001.
[150]邱一华,彭聿平.生理学[M],北京:科学出版社. 2004.
[151] R. Nuccitelli, U. Pliquett, X. H. Chen, et al. Nanosecond pulsed electric fields cause melanomas to self-destruct [J]. Biochemical and Biophysical Research Communications, 2006, 343: 351-360.
[2]乔志恒,范维铭.物理治疗学全书[M].北京:科学技术出版社. 2001.
[3]李力军.现代高新技术治疗恶性肿瘤[M].北京:人民军医出版社. 2003.
[4]张积仁,刘端祺.肿瘤物理治疗新技术[M].北京:人民军医出版社. 2005.
[5]谷铣之,刘泰福,潘国英.肿瘤放射治疗学[M].北京:人民卫生出版社. 1993.
[6]胥彬,许建华.抗癌药物与肿瘤化学治疗进展[M].北京:科学出版社. 2001.
[7]林世寅,李瑞英.现代肿瘤热疗学[M].北京:学苑出版社. 1997.
[8] H. Zhu, K. Zhou, L. Zhang, et al. High intensity focused ultrasound (HIFU) therapy for local treatment of hepatocellular carcinoma: Role of partial rib resection [J]. European Journal of Radiology, 2008, doi:10.1016/j.ejrad.2008.07.003.
[9]邹建中,伍烽,李佩希,廖翠蓉等.超声监控超声聚焦刀治疗肝癌及疗效评价研究[J].中国超声医学杂志, 2000, 16(10): 766-768.
[10]辛育龄.癌症的电化学治疗[M].北京:人民卫生出版社. 1995.
[11]李运泽.电化学治疗恶性肿瘤的研究进展[J].肿瘤研究与临床. 1998, 10(4): 280-282.
[12]宋之乙,辛育龄,李开华,殷瑞,等.直流电治疗恶性肿瘤的研究[J].中华实验外科杂志, 1991, 8(2): 63-64.
[13]辛育龄,权宽宏,宋久卿,等.电化学治疗恶性肿瘤的临床效果[J].中华肿瘤杂志, 1991, 13(6): 467-469.
[14]辛育龄,薛复舟,宋玉忱,等.电化学治疗中晚期肺癌的临床效果[J].中华胸心血管外科杂志, 1997, 13(3): 154-158.
[15]陈国权,徐万成,章五一,等.电化学治疗体表恶性肿瘤的临床疗效[J].癌症, 1994, 13(1): 64-65.
[16] J. C. Weaver. Electroporation of cells and tissues [J]. IEEE Transactions on Plasma Science, 2000, 28(1): 24-33.
[17] L. M. Mir and S. Orlwski. Mechanisms of electrochemotherapy [J]. Advanced Drug Delivery Reviews, 1999, 35: 107-118.
[18] L. M Mir. Electrochemotherapy polentiation of antitumor effect of bleomycin by electric pulses [J]. European Journal of Cancer, 1991, 27(1): 68-72.
[19] M. Belehraclek. Electrochemotherapy: a new antitumor treatment [J]. Cancer, 1993, 72(12): 3694-3700.
[20] E. Neumann and K. Rosenheck. Permeability changes included by electrical pulse in vesicular membranes [J]. Journal of Membrane Biology, 1972, 10: 279-290.
[21] U. Zimmermann, J. Vienken, G. Pilwat. Dielectric breakdown of cell membranes [J]. Biophysical Jourmal, 1974, 14(11): 881-899.
[22] K. J. Kinosita and T. Y. Tsong. Voltage includes formation and hemolysis of human erythocytes [J]. Biochimica et Biophysical Acta., 1979, 471: 227-242.
[23] T. Y. Tsong. Electroporation of cell membranes [J]. Biophysical Journal, 1991, 60: 297-306.
[24] M. Okino. Optimal electric condictions in electrical impulse chemotherapy [J]. Japanese Journal of Cancer Research, 1992, 83(10): 1095-1101.
[25] W. R. Panje, M. P. Hier, G. R. Garman, et al. Electroporation therapy of head and neck cancer [J]. Ann. Otol. Rhinol. Laryngol., 1998, 107: 779-785.
[26] D. Rabussay and S. Kornhauser. Frequently asked questions about electroporation therapy [J]. American Journal of Electromedicine, April 1998: 64-68.
[27] A. J. H. Sale and W. A. Hamilton. Effects of electric fields on microorganizms I killing of bacteria and yeasts [J]. Biochimica et Biophysical Acta., 1967, 118: 781-788.
[28] L. M. Mir, L. F. Glass, G. Ser?a, et al. Effective treatment of cutaneous and subcutaneous malignant tumors by electrochemotherapy [J]. British Journal of Cancer, 1998, 77(12): 2336-2342.
[29] M. Cemazar, D. Miklavcic, L. M. Mir, et al. Electrochemotherapy of tumours resistant to cisplatin: a study in a murine tumour model [J]. European Journal of Cancer, 2001, (37): 1166-1172.
[30] D. ?emrov, and D. Miklav?i?. Calculation of the electrical parameters in electrochemotherapy of solid tumours in mice [J]. Computers in Biology and Medicine, 1998, (28): 439-448.
[31] D. Miklav?i?, D. ?emrov, H. Mekid, et al. A validated model of in vivo electric field distribution in tissues for electrochemotherapy and for DNA electrotranfer for gene therapy [J]. Biochimica et Biophysica Acta., 2000, (1523): 73-83.
[32] T. Kotnik, L. M. Mir, K. Flisar, et al. Cell membrane electropermeabilization by symmetrical bipolar rectangular pulses [J]. Bioelectrochemistry, 2001, 54: 83-90.
[33] D. Miklavcic, D. Semrov, H. Mekid, et al. In vivo electroporation threshold determination [C]. Proceedings of the 22nd annual EMBS International Conference. 2000: 2815-2818.
[34] S. Rodríguez-Cuevas, S. Barroso-Bravo, J. Almanza-Estrada, et al. Electrochemotherapy in primary and metastatic skin tumors [J]: Phase trial using intralesional bleomycin, 2001, 32: 273-276.
[35] M. Marty, G. Sersa, J. R. Garbay, et al. Electrochemotherapy– An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study [J]. European Journal of Cancer (SUPPLEMENTS), 2006, 4: 3-13.
[36] J. R. Garbay, V. Billard, C. Bernat, et al. Successful repetitive treatments by electrochemotherapy of multiple unresectable Kaposi sarcoma nodules [J]. European Journal of Cancer (SUPPLEMENTS), 2006, 4: 29-31.
[37] G. A. Hofmann, S. B. Dev, S. Dimmer, et al. Electroporation therapy: A new approach for the treatment of head and neck cancer [J]. IEEE Transactions on Biomedical Engineering, 1999, 46(6): 752-759.
[38] G. A. Hofmann, and G. Evans. Electronic genetic-physical and biological aspects of cellular electromanipulation [J]. IEEE Engineering of Medical Biology, 1986, 5(4): 6-25.
[39] S. B. Dev, and G. A. Hofmann. Electrochemotherapy– A novel method of cancer treatment [J]. Cancer Treatment Reviews, 1994, 20: 105-115.
[40] R. Heller, R. Gilbert, and M. J. Jaroszeski. Clinical applications of electrochemotherapy [J]. Advanced Drug Delivery Reviews, 1999, 35(1): 119-129.
[41] M. J. Jaroszeski, D. Coppoda, G. Nesmith, et al. Effects of electrochemotherapy with bleomycin on normal liver tissue in a rat model [J]. European Journal of Cancer, 2001, 37: 414-421.
[42] M. J. Jaroszeski, D. Coppoda, C. Pottinger, et al. Treatment of hepatocellular carcinoma in a rat model using electrochemotherapy [J]. European Journal of Cancer, 2001, 37: 422-430.
[43]包家立,胡巧红,梁文权.电穿孔能量对药物经皮渗透速率的影响[J].仪器仪表学报, 2000, 21(5): 546-550.
[44]包家立,梁文权,胡巧红,高建青.经皮给药电穿孔技术的新进展[J].国外医学生物医学工程分册, 1998, 21(4): 222-228.
[45]包家立,梁文权,胡巧红,高建青.经皮给药电穿孔仪的研制[J].仪器仪表学报, 2000, 21(1): 66-69, 77.
[46]高建青,梁文权.促进药物经皮渗透的新方法——电穿孔技术[J].国外医学药学分册, 1997. 24(1): 42-45.
[47]刘长军,王保义,张弘,等.低强度快速电磁脉冲导致细胞电穿孔的研究[J].科学通报, 1999, 44(11): 1157-1161.
[48]汪和睦,汪洲.细胞电穿孔与电融合的机理及应用[J].生物化学与生物物理进展, 1994, 2(14): 322-326.
[49] J. C. Weaver. Electroporation: A dramatic, nonthermal electric field phenomenon [C]. InProceedings of the First World Congress for Electricity and Magnetism in Biology and Medicine. Lake Buena Vista, Florida. Academic Press. 1992.
[50] Y. A. Chizmadzhev. Electric breakdown of bilayer lipid membranes. II. Calculation of the transmembrane lifetime in the steady-state diffusion approximations [J]. Bioelectrochemistry and Bioenergetics, 1979, 6: 53-62.
[51] R. C. Lee. Electrical injury mechanisms: Electrical breakdown of cell membranes [J]. Plast. Reconstr. Surg., 1987, 80: 672-679.
[52] E. Neumann, A. E. Sowers and C. A. Jordan. Electroporation and electrofusion in cell biology [M]. New York. Plenum. 1989.
[53] L. H. Ramirez. Electrochemotherapy on liver tumors in rabbits [J]. British Journal of Cancer, 1998, 77(12): 2104-2111.
[54] G. Sersa. Tumor blood flow change induced by application of electrical pulses [J]. European Journal of Cancer, 1999, 35(4): 672-677.
[55]姚陈果.可控陡脉冲对恶性肿瘤细胞不可逆性电击穿的实验和机理研究[D].博士学位论文.重庆:重庆大学. 2003.6
[56]熊兰.陡脉冲抗肿瘤效应的实验研究和机理分析[D].博士学位论文.重庆:重庆大学. 2004.10.
[57] B. Rubinsky, G. Onik, and P. Mikus. Irreversible electroporation: A new ablation modality - clinical implications [J]. Technology in Cancer Research and Treatment, 2007, 6(1): 37-48.
[58] B. Rubinsky. Irreversible electroporation in medicine [J]. Technology in Cancer Research and Treatment, 2007, 6(4): 255-259.
[59] A. T. Esser, K. C. Smith, T. R. Gowrishankar. Towards solid tumor treatment by irreversible electroporation: Intrinsic redistribution of fields and currents in tissue [J]. Technology in Cancer Research and Treatment, 2007, 6(4): 261-273.
[60] J. F. Edd, R. V. Davalos. Mathematical modeling of irreversible electroporation for treatment planning [J]. Technology in Cancer Research and Treatment, 2007, 6(4): 275-286.
[61] E. Maor, A. Ivorra, J. Leor, B. Rubinsky. The effect of irreversible electroporation on blood vessels [J]. Technology in Cancer Research and Treatment, 2007, 6(4): 307-312.
[62] A. Ivorra, B. Rubinsky. In vivo electrical impedance measurements during and after electroporation of rat liver [J]. Bioelectrochemistry, 2007, 70: 287-295.
[63] A. Ivorra, B. Rubinsky. Electric field modulation in tissue electroporation with electrolytic and non-electrolytic additives [J]. Bioelectrochemistry, 2007, 70: 551-560.
[64] J. F. Edd, L. Horowitz, R. V. Davalos, et al. In vivo results of a new focal tissue ablation technique: Irreversible electroporation [J]. IEEE Transactions on Biomedical Engineering,2006, 53(5): 1409-1415.
[65] R. V. Davalos, L. M. Mir, and B. Rubinsky. Tissue ablation with irreversible electroporation [J]. Annals of Biomedical Engineering, 2005, 33(2): 223-231.
[66] L. Miller, J. Leor, and B. Rubinsky. Cancer cells ablation with irreversible electroporation [J]. Technology in Cancer Research and Treatment, 2005, 4(6): 1-7.
[67] K. H. Schoenbach, S. Xiao, R. P. Joshi, et al. The effect of intense subnanosecond electrical pulses on biological cells [J]. IEEE Transactions on Plasma Science, 2008, 36(2): 414-422.
[68] K. H. Schoenbach, B. Hargrave, R. P. Joshi, et al. Bioelectric effects of intense nanosecond pulses [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2007, 14(5): 1088-1109.
[69] S. J. Beebe, P. M. Fox, L. J. Rec, et al. Nanosecond pulsed electric field (nsPEF) effects on cells and tissues: apoptosis induction and tumor growth inhibition [J]. IEEE Transactions on Plasma Science, 2002, 30(1): 286-292.
[70] K. H. Schoenbach, F. E. Peterkin, R. W. Alden, et al. The effect of pulsed electric fields on biological cells: Experiments and applications [J]. IEEE Transactions on Plasma Science, 1997, 25(2): 284-292.
[71] K. H. Schoenbach, A. A. Ghazala, T. Vithoulkas, et al. The effect of pulsed electrical fields on biological cells [J]. IEEE in press, 1997: 73-78.
[72] K. H. Schoenbach, S. Katsuki, R. H. Stark, et al. Bioelectrics—new applications for pulsed power technology [J]. IEEE Transactions on Plasma Science, 2002, 30(1): 293-300.
[73] K. H. Schoenbach, S. J. Beebe, E. S. Buescher, et al. Intracell effect of ultrashort electrical pulses [J]. Bioelectromagnetics, 2001, 22(6): 440-448.
[74] E. S. Buescher, K. H. Schoenbach. Effects of submicrosecond, high intensity pulsed electric fields on living cells-intracellular electromanipulation [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2003, 10(5): 788-794.
[75] A. G. Pakhomov, A. Phinney, J. Ashmore, et al. Characterization of the cytotoxic effect of high-intensity, 10-ns duration electrical pulses [J]. IEEE Transactions on Plasma Science, 2004, 32(4): 1579-1586.
[76] M. Gundersen. Ultrashort pulse electroporation- applications of high pulsed electric fields to induced caspase activation of human lymphocytes [J]. IEEE Transactions on Plasma Science, 2000, 28(2): 667-670.
[77] N. Chen, K. H. Schoenbach, J. F. Kolb, et al. Leukemic cell intracellular responses to nanosecond electric fields [J]. Biochemical and Biophysical Research Communications, 2004, 317: 421-427.
[78] K. H. Schoenbach, R. P. Joshi, J. F. Kolb, et al. Ultrashort electrical pulses open a new gateway into biological cells [J]. Proceedings of the IEEE, 2004, 92(7): 1122-1137.
[79] E. S. Buescher, R. R. Smith, and K. H. Schoenbach. Submicrosecond intense pulsed electric field effects on intracellular free calcium: Mechanisms and effects [J]. IEEE Transactions on Plasma Science, 2004, 32(4): 1563-1572.
[80] P. T. Vernier, Y. H. Sun, L. Marcu, et al. Calcium bursts induced by nanosecond electric pulses [J]. Biochemical and Biophysical Research Communications, 2003, 310: 286-295.
[81] P. T. Vernier, M. S. Thu, L. Marcu, et al. Nanosecond electroperturbation—mammalian cell sensitivity and bacterial spore resistance [J]. IEEE Transactions on Plasma Science, 2004, 32(4): 1620-1625.
[82] M. Stacey, J. Stickley, P. Foxa, et al. Differential effects in cells exposed to ultra-short, high intensity electric fields: cell survival, DNA damage, and cell cycle analysis [J]. Mutation Research, 2003, 542: 65-75.
[83] R. P. Joshi, Q. Hu, K. H. Schoenbach, et al. Simulations of electroporation dynamics and shape deformations in biological cells subjected to high voltage pulses [J]. IEEE Transactions on Plasma Science, 2002, 30(4): 1536-1546.
[84] R. P. Joshi, Q. Hu, K. H. Schoenbach. Dynamical modeling of cellular response to short-duration, high-intensity electric fields [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2003, 10(5): 778-787.
[85] R. P. Joshi, Q. Hu, R. Aly, et al. Self-consistent simulations of electroporation dynamics in biological cells subjected to ultrashort electrical pulses [J]. Physical Review, 2001, 64, 011913.
[86] R. P. Joshi, Q. Hu, K. H. Schoenbach. Modeling studies of cell response to ultrashort, high-intensity electric fields—implications for intracellular manipulation [J]. IEEE Transactions on Plasma Science, 2004, 32(4): 1677-1686.
[87] J. F. R. Kerr, A. H. Wyllie, and A. R. Currie. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics [J]. British Journal of Cancer, 1972, 26: 239-257.
[88]彭黎明,王曾礼.细胞凋亡的基础与临床[M].北京:人民卫生出版社. 2000.
[89]胡野,凌志强,单小云.细胞凋亡的分子医学[M].北京:军事医学科学出版社. 2002.
[90]肖华娟,严萍,张适昌.纳秒脉冲细胞内电处理机理及其研究进展[J].高电压技术, 2004, 30(4): 39-41, 72.
[91] T. Kotnik, D. Miklavcic, T. Slivnik. Time course of transmembrane voltage induced by time-varying electric fields—a method for theoretical analysis and its application [J]. Bioelectrochemistry and Bioenergetics, 1998, 45: 3-16.
[92] L. M. Mir, S. Orlowski, J. Belehradek, et al. Biomedical applications of electric pulses with special emphasis on antitumor electrochemotherapy [J]. Bioelectrochemistry and Bioenergetics, 1995, 38: 203-207.
[93] G. Sersa, B. Stabuc, M. Cemazar, et al. Electrochemotherapy with cisplatin: Clinical experience in malignant melanoma patients [J]. Clinical Cancer Research, 2000, 6: 863-867.
[94] D. Miklavcic, K. Beravs, D. Semrov, et al. The importance of electric field distribution for effective in vivo electroporation of tissues [J]. Biophysical Journal, 1998, 74: 2152-2158.
[95] T. Kotnik, D. Miklavcic. Analytical description of transmembrane voltage induced by electric fields on spheroidal cells [J]. Biophysical Journal, 2000, 79: 670-679.
[96] K. Cheng. A biomechanical model of electroporation of a biological membrane [J]. IEEE in press, 1997: 70-73.
[97] K. Cheng. An improved biophysical model of electroporation of cell membrane [C]. Proceedings of the 18th annual EMBS International Conference, 1996: 1915-1916.
[98] K. Cheng. Development of biomechanical models of electroporation [J]. IEEE in press, 1995: 183-184.
[99]冯慈璋.电磁场[M].北京:高等教育出版社. 1994.
[100]邱关源.电路(第四版) [M].北京:高等教育出版社. 1999.
[101] A. L. Hodgkin, and A. F. Huxley. A quantitative description of ion currents and its applications to conduction and excitation in nerve membranes [J]. Journal of Physiology, 1952, 117: 500-544.
[102] H. Kanai, K. Sakamoto, M. Haeno, et al. Electrical measurement of fluid distribution in human legs: Estimation of extra- and intra-cellular fluid volume [J]. Journal of Microwave Power, 1983, 18(3): 235-248.
[103] K. R. Foster. Thermal and nonthermal mechanism of interaction of radio-frequency energy with biological systems [J]. IEEE Transactions on Plasma Science, 2000, 28(1): 15-23.
[104] I. Ermolina, Y. Polevaya, Y. Feldman, et al. Study of normal and malignant white blood cells by time domain dielectric spectroscopy [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2001, 8(2): 253-261.
[105] Y. Feldman, I. Ermolina, Y. Hayashi. Time domain dielectric spectroscopy study of biological systems [J]. IEEE Transactions on Dielectrics and Electrical Insulation, 2003, 10(5): 728-753.
[106]王莹.高功率脉冲电源[M].北京:原子能出版社. 1991.
[107]曾正中.实用脉冲功率技术引论[M].西安:陕西科学技术出版社. 2003.
[108]刘锡三.高功率脉冲技术[M].北京:国防工业出版社. 2005.
[109]周璧华,陈彬,石立华.电磁脉冲及其工程防护[M].北京:国防工业出版社. 2003.
[110]杨绍洲,廖伟光.加速器中闸流管的原理和维护[J].医疗设备信息, 2004, 19(7): 73-74.
[111]詹伟国.浅谈加速器中的氢闸流管[J].医疗装备, 2003, 12:47-48.
[112]李序宝,赵永健.电力电子器件及其应用[M].北京:机械工业出版社. 1996.
[113]沙占友.数字电位器设计原理与应用[M].北京:机械工业出版社. 2007.
[114]李树靖,林凌,李刚.线性光耦合器LOC110的原理与应用[J].世界电子元器件. 2002, 12: 44-46.
[115]潘耀谦,高丰,成军.细胞凋亡与细胞坏死比较的研究进展[J].动物医学进展, 2000, 21(4): 5-8.
[116] M. O. Hengartner. The biochemistry of apoptosis [J]. Nature, 2000, 407(6805): 770-776.
[117] A. G. Letai. Diagnosing and exploiting cancer's addiction to blocks in apoptosis [J]. Nature Reviews Cancer, 2008, 8: 121-132.
[118] M. S. Runge, and W, C, Patterson. Principles of molecular medicine (second edition) [M]. Totowa: Humana Press, 2006.
[119] F. L. Kiechle, and X. B. Zhang. Apoptosis: Biochemical aspects and clinical implications [J]. Clinica Chimica Acta, 2002, 326: 27-45.
[120] C. Twomey and J. V. McCarthy. Pathways of apoptosis and importance in development [J]. Journal of Cellular and Molecular Medicine, 2005, 9(2): 345-359.
[121] R. J. Bold, P. M. Termuhlen, and D. J. McConkey. Apoptosis, cancer and cancer therapy [J]. Surgical Oncology, 1997, 6: 133-142.
[122]张丽杰,赵振军.细胞凋亡与肿瘤发生及治疗新策略[J].临床荟萃, 2003, 18(7): 416-417.
[123] D. V. Krysko, T. V Berghe, K. D’Herde, et al. Apoptosis and necrosis: Detection, discrimination and phagocytosis [J]. Methods, 2008, 44(3): 205-221.
[124]辛华.细胞生物学实验[M].北京:科学出版社. 2001.
[125] N. Kaise, I. S. Edelman. Calcium dependence of glueocorticoid - induced lymphocytolysis [J]. Proceedings of the National Academy of Sciences of the United States of America, 1977, 74: 638-642.
[126] J. Krebs. The role of calcium in apoptosis [J]. BioMetals, 1998, 11: 375-382.
[127]郭静,蒲咏梅,张东才.钙离子信号与细胞凋亡[J].生物物理学报, 2005, 21(1): 1-18.
[128]张帅,崔隽,沈萍萍.细胞凋亡中的钙离子调控[J].细胞生物学杂志, 2007, 29: 785-790.
[129] L. Li, Y. C. Tian, M. O. Tadé, et al. Apoptosis of tumor cells by temperature and anti-tumor drug: microscopic and macroscopic investigations [J]. Journal of Thermal Biology, 2003, 28:321-329.
[130] Y. W. Liu, C. X. Wang, C. Y. Zheng, et al. Microcalorimetric study of the metabolism of U-937 cells undergoing apoptosis induced by the combined treatment of hyperthermia and chemotherapy [J]. Journal of Thermal Biology, 2002, 27: 129-135.
[131]邹丽娟,陈亚敏,徐晓颖,等.温热顺铂对肝癌细胞的杀伤效应及其诱导凋亡的研究[J].肿瘤防治研究, 2002, 29(1): 12-14.
[132] T. Sakurai, K. Itoh, Y. Liu, et al. Low temperature protects mammalian cells from apoptosis initiated by various stimuli in vitro [J]. Experimental Cell Research, 2005, 309: 264-272.
[133]高凌云,张洪,许国英,等.不同脑温对全脑缺血再灌注后相关基因及细胞凋亡的影响[J].福建医科大学学报, 2001, 35(2): 104, 108.
[134] A. K. Zaidi, R. S. Bagewadikar, M. Subramanian, et al. Effect of whole body hyperthermia (39℃, 1h) on radiation-induced apoptosis in Swiss mice [J]. Journal of Thermal Biology, 2004, 29: 3-8.
[135] A. Dieing, O. Ahlers, T. Kerner, et al. Whole body hyperthermia induces apoptosis in subpopulations of blood lymphocytes [J]. Immunobiology, 2003, 207: 265-273.
[136]刘晓翌,刘建军. Caspase与细胞凋亡[J].武汉大学学报(医学版), 2004, 25(6): 742-745.
[137]袁长青,丁振华. Caspase的活化及其在细胞凋亡中的作用[J].生理科学进展, 2002, 33(3): 220-224.
[138] Chen M, Wang J. Initiator caspases in apoptosis signaling pathways [J]. Apoptosis, 2002, 7(4): 313-319.
[139]李小明,孙志贤.细胞凋亡中的关键蛋白酶-Caspase-3 [J].国外医学分子生物学分册, 1999, 21(1): 6-9.
[140]戴锅生.传热学[M].北京:高等教育出版社. 1999.
[141] H. H. Pennes. Analysis of tissue and arterial blood temperatures in the resting forearm [J]. Journal of Applied Physiology, 1948, 1: 93-122.
[142] J. C.切托.生物传热学[M].北京:科学出版社. 1991.
[143]王存诚,陈槐卿.生物医学中的热物理探索[M].北京:科学出版社. 1994.
[144] R. V. Davalos, B. Rubinsky, and L. M. Mir. Theoretical analysis of the thermal effects during in vivo tissue electroporation [J]. Bioelectrochemistry, 2003, 61: 99-107.
[145] S. Tungjitkusolmun, S. T. Staelin, D. Haemmerich, et al. Three-dimensional finite-element analyses for radio-frequency hepatic tumor ablation [J]. IEEE Transactions on Biomedical Engineering, 2002, 49: 3-9.
[146]李辑熙,牛中奇.生物电磁学概论[M].西安:西安电子科技大学出版社. 1990.
[147]李和杰,张学学,伊耀繁.体表常热流法无损检测血液灌注率实验研究[J].中国生物医学工程学报, 2003, 22(5):393-398.
[148]杨昆,刘伟,朱光明.生物组织血液灌注率的无损测量研究[J].工程热物理学报, 2003, 24(1): 69-72.
[149]陈品健.动物生物学[M],北京:科学出版社. 2001.
[150]邱一华,彭聿平.生理学[M],北京:科学出版社. 2004.
[151] R. Nuccitelli, U. Pliquett, X. H. Chen, et al. Nanosecond pulsed electric fields cause melanomas to self-destruct [J]. Biochemical and Biophysical Research Communications, 2006, 343: 351-360.