硼中子俘获治疗中细胞损伤的Monte Carlo模拟与分析
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摘要
理想的肿瘤治疗方法应能够选择性地杀死肿瘤细胞，而几乎不损害周围正常组织的结构与功能。目前临床上常用的放疗方法如~(60)Co、X射线、立体定向放射治疗等，很难做到二者兼顾。而硼中子俘获治疗技术(Boron Neutron Capture Therapy，简称BNCT)的特点是在肿瘤细胞内发挥作用，基本上不会损伤正常细胞，因此，BNCT技术作为一种前景广阔的放疗手段，越来越受到世界各国重视。
掌握Li离子及α粒子在细胞和亚细胞水平上的微观剂量分布及细胞内微观损伤分布，是改善BNCT疗效的重要环节，因而微剂量学研究是BNCT领域中一大研究热点。在微观上，载能离子与生物体相互作用的原初物理过程，是研究微剂量学及其相关生物效应的基础。然而由于实验设备及技术手段的制约，目前，对于载能离子在细胞和亚细胞水平上的微观作用过程，还不能精确地观察及测量。因此，本工作首先建立精确的人体肿瘤细胞模型，借助先进的计算机技术，采用基于Monte Carlo方法的SRIM程序精确模拟了BNCT中载能离子与细胞相互作用的物理过程，通过分析粒子的射程分布、径迹结构、细胞内损伤情况以及微观剂量分布等，研究了肿瘤细胞的各种生物效应，此外，还模拟了当硼原子位于细胞中不同位置时，在肿瘤细胞中的能量沉积及细胞的损伤情况，通过分析得到有意义的结论，从而为BNCT的进一步研究提供了基本数据和理论依据。
The best therapy technique for tumor can kill tumor cells and has only minor effect on healthy cells. It doesn't meet the two requirements above at the same time for conventional radiation treatment such as 60Co therapy , X ray therapy and stereotactic radiosurgery & radiotherapy at present. Boron neutron capture therapy (BNCT) has a promising development in tumor treatment for it can achieve selectivity at the cellular level.
It's very important for BNCT to know the microdosimetry and damage distributing at cellular and subcellular level. The physics process of interaction between energetic ions and tumor cells provides the foundation for researching the microdosimetry and relative biological effect. For lack of laboratory apparatus and technique, it's very hard to observe the micro-process between energetic ions and tumor cells at present. So the interaction between -particle produced from the 10B(n, )7Li neutron capture reaction and tumor cells has been simulated by SRIM code based on Monte Carlo technique in this paper. The biological effect of tumor cells has been studied by analyzing the track and depth of the particles, the deposition of energy and the damage of target. And the deposited energy of the a -particles in the different position of the cell model has also been calculated by the SRIM code in this paper and the structure damage to the tumor cell has been simulated. The computed results are compared and analyzed. The results are very helpful to understand the distribution of microdosimetry at cellular and subcellular level. And this would provide theory and support for BNCT.
掌握Li离子及α粒子在细胞和亚细胞水平上的微观剂量分布及细胞内微观损伤分布，是改善BNCT疗效的重要环节，因而微剂量学研究是BNCT领域中一大研究热点。在微观上，载能离子与生物体相互作用的原初物理过程，是研究微剂量学及其相关生物效应的基础。然而由于实验设备及技术手段的制约，目前，对于载能离子在细胞和亚细胞水平上的微观作用过程，还不能精确地观察及测量。因此，本工作首先建立精确的人体肿瘤细胞模型，借助先进的计算机技术，采用基于Monte Carlo方法的SRIM程序精确模拟了BNCT中载能离子与细胞相互作用的物理过程，通过分析粒子的射程分布、径迹结构、细胞内损伤情况以及微观剂量分布等，研究了肿瘤细胞的各种生物效应，此外，还模拟了当硼原子位于细胞中不同位置时，在肿瘤细胞中的能量沉积及细胞的损伤情况，通过分析得到有意义的结论，从而为BNCT的进一步研究提供了基本数据和理论依据。
The best therapy technique for tumor can kill tumor cells and has only minor effect on healthy cells. It doesn't meet the two requirements above at the same time for conventional radiation treatment such as 60Co therapy , X ray therapy and stereotactic radiosurgery & radiotherapy at present. Boron neutron capture therapy (BNCT) has a promising development in tumor treatment for it can achieve selectivity at the cellular level.
It's very important for BNCT to know the microdosimetry and damage distributing at cellular and subcellular level. The physics process of interaction between energetic ions and tumor cells provides the foundation for researching the microdosimetry and relative biological effect. For lack of laboratory apparatus and technique, it's very hard to observe the micro-process between energetic ions and tumor cells at present. So the interaction between -particle produced from the 10B(n, )7Li neutron capture reaction and tumor cells has been simulated by SRIM code based on Monte Carlo technique in this paper. The biological effect of tumor cells has been studied by analyzing the track and depth of the particles, the deposition of energy and the damage of target. And the deposited energy of the a -particles in the different position of the cell model has also been calculated by the SRIM code in this paper and the structure damage to the tumor cell has been simulated. The computed results are compared and analyzed. The results are very helpful to understand the distribution of microdosimetry at cellular and subcellular level. And this would provide theory and support for BNCT.
引文
[1] 牛金昭．癌治疗慎选择．科学时报．2000年9月1日
[2] 蔡如鹏．挑战癌症禁区．科学时报．1999年1月31日
[3] 殷蔚伯．重离子治疗，第145次“重离子束治癌”香山科学会议．北京，2000年9月12-14．P6
[4] A.J.M. Vermoken and F.A.T.M. Schermer (ed.). Towards coordination of cancer research in Europe. IOS Press, Ansterdam, 1994.
[5] 全自动多叶准直医学理论：http://www.eti.com.cn/radiation/mlcmedical.htm 2004年2月
[6] 许昌韶．肿瘤放射治疗学．北京：原子能出版社．1995
[7] 于金明，于甬华．放疗设备及放疗技术的进展．国外医学肿瘤学分册．Vol(27)，No1，2000
[8] 李宝生，于金明，王立英等．调强放射治疗计划．中国肿瘤．Vol(10)，No8，2001
[9] 张纯祥．微剂量学研究的进展．核物理动态．1993年3月，Vol 10，No．1
[10] ICRU Report 36 Microdosimetry, 1983
[11] 吉永星．医用电子直线加速器剂量学的研究 (硕士论文)．北京大学，2000
[12] Nelson WR, Hirayama H, Rogers DWO. The EGS4 code system, Standford Linear Accelerator Center Report SLAC-256, 1985
[13] LANL, X-Group. MCNP-A general Monte Carlo Code for neutron and photon transport, LA-7396-M, 1979
[14] Briesmeister JT. MCNP-A general Monte Carlo N-particle transport code. Version 4A, Los Alarnos National Laboratory Report, LS 12625, 1993.
[15] Harmann Siantar CL, Bergstrom PM, Chandler PM, et al. Lawrence Livermore National Laboratory's PEREGRINE project, in Proceedings of 12th International Conference on the Use of Computers in Radiation Therapy, Salt City, UT, may, 1997.
[16] I. Kawrakow, M. Fippel. VMC++, a fast MC algorithm for Radiation Treatment planning. Proc. 13th Int. Conf. on the Use of Computers in Radiation Therapy (ICCR), Heidelberg, 126-128 (2000) .
[17] I. Kawrakow, M. Fippel. VMC++, a MC algorithm optimized for electron and photon beam dose calculations for RTP. World Congress on Medical Physics and Biomedical Engineering, Chicago, Illinois, USA 2000.
[18] 张晓峰，袁树斌，雷进等．硼中子俘获治疗．中华神经外科杂志，1999年7月，Vol15，No．4
[19] RolfF Barth，Albert H Soloway，Weilian Yang．中华放射肿瘤学杂志，硼中子俘获治疗脑肿瘤的现状与前景．1998年12月，Vol 7，No．4
[20] P.D.Bradley, and A.B.Rosenfeld. The equivalence correction for silicon microdosimetry detectors in boron neutron capture therapy.
[21] Barth RF, et al. Cancer Res, 1990.50:1061
[22] 李贵平．肿瘤硼中子俘获疗法的研究现状．医学综述．1998，Vol 4，No．8
[23] Soloway AH, Barty RF, Gahbauer RA, et al. The rationale and requirements for the development
of boron neutron capture therapy of brain trmors. J Neurooncol, 1997, 33:9-18
[24] Barth RF, Soloway AH. Boron neutron capture therapy of brain trmors current status and future prospects. J Neurooncol, 1997, 33: 3-7.
[25] Barth RF, Soloway AH.Brugger RM. Boron neutron capture therapy of brain tumors: past history, current status, and future potential. Cancer Invest, 1996, 4:534-550
[26] Hartman T. and Carlsson J. Radiation dose heterogeneity in receptor and antigen mediated boron neutron capture therapy. Radiotherapy and Ontology, 1994, 31 : 61-75.
[27] Bleuel DL, Donahue RJ, Ludewigt BA, et al. Designing accelerator based epithermal neutron beams for boron neutron capture therapy. Med Phys. 1998, 25:1725-1734
[28] Yu w, Yue G, Han X, et al. Measurements of the neutron yields from 7Li (p, n) 7Be reaction (thick target) with incident energies from 1.885 to 2.0 MeV. Med Phys. 1998, 25:1222-1224
[29] 卢希庭．原子核物理．北京：原子能出版社．2000年10月
[30] 王贻华，胡正琼．离子注入与分析基础．北京：航空工业出版社．1992
[31] 万发荣．金属材料的辐射损伤．北京：科学出版社．1993年12月
[32] 余增亮．离子束生物技术引论．安徽：科学技术出版社．1996年7月
[33] 余增亮．离子束与生命科学——一个新的研究领域．物理，1997，26 (6)，333-338
[34] 袁士斌．重离子注入生物材料质量沉积效应评述．核技术，2002，25(12)
[35] 杨抚华，胡以平．医学细胞生物学．北京：科学出版社．2002，3
[36] 翟中和．细胞生物学．北京：高等教育出版社．2001，5
[37] 崔学增．医学细胞生物学教程．北京：中国医药科技出版社．1992，3
[38] 江希明．肿瘤生物学．浙江：浙江科学技术出版社．1990年12月
[39] 汤钊猷．现代肿瘤学．上海：上海医科大学出版社．2000年9月
[40] 夏寿萱．放射生物学．北京：军事医学科学出版社．1998年8月
[41] 吴德昌．放射医学．北京：军事医学科学出版社．2001年3月
[42] 裴鹿成，张孝泽．蒙特卡罗方法及其在粒子输运问题中的应用．北京：科学出版社．1980
[43] J.F. Ziegler, et al. The Stopping and Range of Ions in Solids. New York: Pergamon Press. 1996
[44] 卢希庭．原子核物理．北京：原子能出版社，2000
[45] Reinhard L. The Conformation of Membrane. Nature, 1991, 349:7
[46] Crister P Ceberg, Anders Persson, Arne Brun, et al. A stochastic model for subcellular dosimetry in boron neutron capture therapy. Phys Med Biol. 40(1995) 1819-1830
[47] Tien Nguyen, Gordon L. Browneil, Sylvia A. Holden, et al. Subceilular Distribution of Various Boron Compounds and Implications for Their Efficacy in Boron Neutron Capture Therapy by Monte Carlo Simulations. Radist Res. 133(1993), 33-40
[48] F.Poller, W. Sauerwein. Monte Carlo Simulation of the Biological Effects of Boron Neutron Capture Irradiation with d(14)+Be Neutrons In Vitro. Radist Res. 142(1995), 98-106
[49] 韩光武，马受武，卫增泉等．核技术，1995，18(12)，759-764
[50] 刘长军，王保义．四川大学学报，1998，35(1)，55-60
[51] 韩光武，卫增泉，马受武等．核技术，1996，19(3)，147-151
[52] 韩光武．马受武，卫增泉．核技术，1996，19(3)，152-154
[53] ICRP 1975 Report of the Task Group on Reference Man. ICRP Publication 23
[54] Uwe Schneider, Eros Pedroni, Antony Lomax. Phys Med Biol. 41(1996) 111-124
[55] Peter D, Bradley. A thesis of the degree Doctor of Philosophy from University of Wollongong. 2000
[56] 卫增泉，刘玉岩等．辐射研究与辐射工艺学报，1993，11(2)：90
[57] Feinendegen L E. The cell dose concept; potential application in radiation protection. Phys Med Bid. 35 597-612(1990)
[58] Rossi H H, Zaider M. Elements of microdosimetry .Med Phys. 18 (I991) 1085-92
[59] Kellerer A M. Rossi H H. A generalized formulation of dual radiation action. Radial Res. 75(1978) 411-88
[60] Bond V P, Varma M N, Sondhaus C A and Feinendegen L E An alternative to absorbed dose, quality and RBE at low exposures. Radial Res. 104(1985) 52-57
[61] Gabel D, Foster S and Fairchild R G. The Monte Carlo simulation of the biological effect of the10B(n, a)7Li reaction in cells and tissues and its implication for boron neutron capture therapy. Radiat Res. 111(1987) 14-25
[62] Vroegindeweij C, Wheeler F J. Microdosimetry Model for Boron Neutron Capture Therapy: 1 .Determination of Microscopic Quantities of Heavy Particles on a Cellular Scale. Radiat Res, 2001,155:490-497
[2] 蔡如鹏．挑战癌症禁区．科学时报．1999年1月31日
[3] 殷蔚伯．重离子治疗，第145次“重离子束治癌”香山科学会议．北京，2000年9月12-14．P6
[4] A.J.M. Vermoken and F.A.T.M. Schermer (ed.). Towards coordination of cancer research in Europe. IOS Press, Ansterdam, 1994.
[5] 全自动多叶准直医学理论：http://www.eti.com.cn/radiation/mlcmedical.htm 2004年2月
[6] 许昌韶．肿瘤放射治疗学．北京：原子能出版社．1995
[7] 于金明，于甬华．放疗设备及放疗技术的进展．国外医学肿瘤学分册．Vol(27)，No1，2000
[8] 李宝生，于金明，王立英等．调强放射治疗计划．中国肿瘤．Vol(10)，No8，2001
[9] 张纯祥．微剂量学研究的进展．核物理动态．1993年3月，Vol 10，No．1
[10] ICRU Report 36 Microdosimetry, 1983
[11] 吉永星．医用电子直线加速器剂量学的研究 (硕士论文)．北京大学，2000
[12] Nelson WR, Hirayama H, Rogers DWO. The EGS4 code system, Standford Linear Accelerator Center Report SLAC-256, 1985
[13] LANL, X-Group. MCNP-A general Monte Carlo Code for neutron and photon transport, LA-7396-M, 1979
[14] Briesmeister JT. MCNP-A general Monte Carlo N-particle transport code. Version 4A, Los Alarnos National Laboratory Report, LS 12625, 1993.
[15] Harmann Siantar CL, Bergstrom PM, Chandler PM, et al. Lawrence Livermore National Laboratory's PEREGRINE project, in Proceedings of 12th International Conference on the Use of Computers in Radiation Therapy, Salt City, UT, may, 1997.
[16] I. Kawrakow, M. Fippel. VMC++, a fast MC algorithm for Radiation Treatment planning. Proc. 13th Int. Conf. on the Use of Computers in Radiation Therapy (ICCR), Heidelberg, 126-128 (2000) .
[17] I. Kawrakow, M. Fippel. VMC++, a MC algorithm optimized for electron and photon beam dose calculations for RTP. World Congress on Medical Physics and Biomedical Engineering, Chicago, Illinois, USA 2000.
[18] 张晓峰，袁树斌，雷进等．硼中子俘获治疗．中华神经外科杂志，1999年7月，Vol15，No．4
[19] RolfF Barth，Albert H Soloway，Weilian Yang．中华放射肿瘤学杂志，硼中子俘获治疗脑肿瘤的现状与前景．1998年12月，Vol 7，No．4
[20] P.D.Bradley, and A.B.Rosenfeld. The equivalence correction for silicon microdosimetry detectors in boron neutron capture therapy.
[21] Barth RF, et al. Cancer Res, 1990.50:1061
[22] 李贵平．肿瘤硼中子俘获疗法的研究现状．医学综述．1998，Vol 4，No．8
[23] Soloway AH, Barty RF, Gahbauer RA, et al. The rationale and requirements for the development
of boron neutron capture therapy of brain trmors. J Neurooncol, 1997, 33:9-18
[24] Barth RF, Soloway AH. Boron neutron capture therapy of brain trmors current status and future prospects. J Neurooncol, 1997, 33: 3-7.
[25] Barth RF, Soloway AH.Brugger RM. Boron neutron capture therapy of brain tumors: past history, current status, and future potential. Cancer Invest, 1996, 4:534-550
[26] Hartman T. and Carlsson J. Radiation dose heterogeneity in receptor and antigen mediated boron neutron capture therapy. Radiotherapy and Ontology, 1994, 31 : 61-75.
[27] Bleuel DL, Donahue RJ, Ludewigt BA, et al. Designing accelerator based epithermal neutron beams for boron neutron capture therapy. Med Phys. 1998, 25:1725-1734
[28] Yu w, Yue G, Han X, et al. Measurements of the neutron yields from 7Li (p, n) 7Be reaction (thick target) with incident energies from 1.885 to 2.0 MeV. Med Phys. 1998, 25:1222-1224
[29] 卢希庭．原子核物理．北京：原子能出版社．2000年10月
[30] 王贻华，胡正琼．离子注入与分析基础．北京：航空工业出版社．1992
[31] 万发荣．金属材料的辐射损伤．北京：科学出版社．1993年12月
[32] 余增亮．离子束生物技术引论．安徽：科学技术出版社．1996年7月
[33] 余增亮．离子束与生命科学——一个新的研究领域．物理，1997，26 (6)，333-338
[34] 袁士斌．重离子注入生物材料质量沉积效应评述．核技术，2002，25(12)
[35] 杨抚华，胡以平．医学细胞生物学．北京：科学出版社．2002，3
[36] 翟中和．细胞生物学．北京：高等教育出版社．2001，5
[37] 崔学增．医学细胞生物学教程．北京：中国医药科技出版社．1992，3
[38] 江希明．肿瘤生物学．浙江：浙江科学技术出版社．1990年12月
[39] 汤钊猷．现代肿瘤学．上海：上海医科大学出版社．2000年9月
[40] 夏寿萱．放射生物学．北京：军事医学科学出版社．1998年8月
[41] 吴德昌．放射医学．北京：军事医学科学出版社．2001年3月
[42] 裴鹿成，张孝泽．蒙特卡罗方法及其在粒子输运问题中的应用．北京：科学出版社．1980
[43] J.F. Ziegler, et al. The Stopping and Range of Ions in Solids. New York: Pergamon Press. 1996
[44] 卢希庭．原子核物理．北京：原子能出版社，2000
[45] Reinhard L. The Conformation of Membrane. Nature, 1991, 349:7
[46] Crister P Ceberg, Anders Persson, Arne Brun, et al. A stochastic model for subcellular dosimetry in boron neutron capture therapy. Phys Med Biol. 40(1995) 1819-1830
[47] Tien Nguyen, Gordon L. Browneil, Sylvia A. Holden, et al. Subceilular Distribution of Various Boron Compounds and Implications for Their Efficacy in Boron Neutron Capture Therapy by Monte Carlo Simulations. Radist Res. 133(1993), 33-40
[48] F.Poller, W. Sauerwein. Monte Carlo Simulation of the Biological Effects of Boron Neutron Capture Irradiation with d(14)+Be Neutrons In Vitro. Radist Res. 142(1995), 98-106
[49] 韩光武，马受武，卫增泉等．核技术，1995，18(12)，759-764
[50] 刘长军，王保义．四川大学学报，1998，35(1)，55-60
[51] 韩光武，卫增泉，马受武等．核技术，1996，19(3)，147-151
[52] 韩光武．马受武，卫增泉．核技术，1996，19(3)，152-154
[53] ICRP 1975 Report of the Task Group on Reference Man. ICRP Publication 23
[54] Uwe Schneider, Eros Pedroni, Antony Lomax. Phys Med Biol. 41(1996) 111-124
[55] Peter D, Bradley. A thesis of the degree Doctor of Philosophy from University of Wollongong. 2000
[56] 卫增泉，刘玉岩等．辐射研究与辐射工艺学报，1993，11(2)：90
[57] Feinendegen L E. The cell dose concept; potential application in radiation protection. Phys Med Bid. 35 597-612(1990)
[58] Rossi H H, Zaider M. Elements of microdosimetry .Med Phys. 18 (I991) 1085-92
[59] Kellerer A M. Rossi H H. A generalized formulation of dual radiation action. Radial Res. 75(1978) 411-88
[60] Bond V P, Varma M N, Sondhaus C A and Feinendegen L E An alternative to absorbed dose, quality and RBE at low exposures. Radial Res. 104(1985) 52-57
[61] Gabel D, Foster S and Fairchild R G. The Monte Carlo simulation of the biological effect of the10B(n, a)7Li reaction in cells and tissues and its implication for boron neutron capture therapy. Radiat Res. 111(1987) 14-25
[62] Vroegindeweij C, Wheeler F J. Microdosimetry Model for Boron Neutron Capture Therapy: 1 .Determination of Microscopic Quantities of Heavy Particles on a Cellular Scale. Radiat Res, 2001,155:490-497