近31年來，惡性腫瘤一直在台灣國人十大死因中高居榜首，如何更有效的治療癌症成為了眾人關心的課題。放射性的腫瘤標靶治療能夠有效的針對特定的腫瘤細胞進行治療，利用例如免疫標誌的方式，將放射性核種送到目標的腫瘤細胞附近，使腫瘤能夠更準確、更加集中的接受到放射劑量，而達到殺死腫瘤細胞，治癒癌症的目的；因此選用一個合適的核種去進行治療成為一個值得研究的方向。
過去的研究對於能夠發射出鄂惹電子的核種，對於細胞所造成的生物效應感到十分感興趣，為了能夠更好的去評估各種核種在放射治療上的潛力，我們提出了一個利用局部損傷模型的演算法，使用這個模型為將能夠發射出鄂惹電子的核種均勻分佈在細胞中，以同心球體的方式將細胞分成多層結構，用以計算核種在各層所造成的局部劑量，進而得到核種在細胞中造成的吸收劑量，以及核種單次衰變對於細胞造成各種形式的DNA損傷產率。
選用了五種核種去進行評估，分別為：125I、119Sb、123I、111In和 99mTc，使用了兩種蒙地卡羅方法：先利用Penolope code對於各個核種放出的鄂惹電子對於細胞產生的細胞S值進行計算，這個混合型的演算法結合了事件對事件方法(event by event)、以及多重散射理論模型(multiple scattering theory)，能對於非常低能量的電子進行模擬；使用MCDS(Monte Carlo Damage simulation )code計算不同能量對於細胞造成各種形式的DNA損傷的產率，MCDS測量的方式是利用從詳細的軌道結構模擬(track structure)的方式得到的趨勢性，從而計算DNA的損傷。
將使用這種計算法所得到的細胞S值以及DNA損傷的產率與過去已經發表的資料去做比較，細胞S值所得到的結果與利用其他數學分析法、蒙地卡羅方法、實驗結果的資料比較後的差異範圍大概會是在8%以內，而結合兩個演算法得到的結果與其他已經發表的資料比較起來，大致上的結果是準確的，雖然會有點誤差性存在，這個方法可以藉由MCDS得到的結果，評估各個核種之間的相對生物效應，對於核種的選擇上提供幫助。
這種方式我們認為是能夠有效，並且可以使用各種能夠發射鄂惹電子核種的頻譜，預測在不同的環境結構下，例如：單層細胞模型，得到各核種所造成各種不同DNA損傷的產率。希望在未來對於放射性腫瘤標靶治療方式的核種選擇上，能夠提供一個有效且方便的計算法。

In this thesis, an algorithm methodology was proposed to estimate the absorbed does to help selecting a suitable nuclide on radionuclide target therapy. Past studies were interested in the biological effectiveness on cells by the Auger-electron emitting nuclides. As to radiation treatment, for a better estimation on therapeutic potential of various types of radionuclide, we proposed an algorithm by used local damage model. Used this model, the radiation source was assumed to be uniform distributed over cells in the way of concentric spheres to divide cells into multiple-shell structure. We could calculate the absorbed does produced by nuclide on each structural shell of cells, and various types of DNA clustered damage yields by per decay of radionuclide.

We chose the five kinds of radionuclides to estimate: 125I, 119Sb, 123I, 111In, and 99mTc, and use two kinds Monte Carlo code. First of all, by way of Penolope (Penetration and ENErgy LOss of Positrons and Electrons) code , we could calculate the subcellular absorbed dose and cellular S value from radiation by each Auger-electrons emitting radionuclide. This mixed simulation algorithm combined an event by event simulation for hard collisions and multiple scattering theory for soft collisions, could be simulated for very low energy electrons. Monte Carlo damage simulation (MCDS) damage simulation code was applied to estimate the nucleotide-level maps of clustered DNA damage yields caused by different energy. To estimate the DNA damage data, MCDS employed the tendency of the DNA damage spectrum from the detailed track structural simulation ,such method will relatively simple and efficient.

The calculated S value and DNA damage yields had been compared with published data. The estimated cellular S values outcome would be probably less than 8% discrepancy of previous outcome from other mathematical analysis, Monte Carlo method and the experimental data. Compared with other published data, the outcome from the combination of two algorithms, was generally found accurate although some discrepancy existed. In terms of the MCDS outcome, this method could evaluate the relative biological effectiveness of each radionuclide and assist in the selection of radionuclide.

誌謝………………………………………………………………………I
中文摘要………………………………………………………………III
Abstract…………………………………………………………………V
壹、緒論………………………………………………………………1-8
一、前言…………………………………………………………………1
二、鄂惹電子(Auger-electron)的基本特性……………………………2
三、核種的選擇…………………………………………………………4
四、DNA損傷(DNA damage) …………………………………………5
貳、研究動機……………………………………………………………9
叁、材料與方法………………………………………………………10-18
一、細胞模型－局部損傷模型（Local damage model , LDM ) ………10
二、細胞劑量學 (Cellular Dosimetry) ………………………………13
三、蒙地卡羅方法(Monte Carlo method) ………………………………15
四、混合演算法-Penelope 程式………………………………………18
五、蒙地卡羅損傷模擬程式……………………………………………23
肆、 實驗結果………………………………………………………27-39
一、Penelope演算法測試………………………………………………27
二、細胞的S值…………………………………………………………29
三、DNA損傷的產率……………………………………………………31
伍、討論 ……………………………………………………………39-43
陸、圖目錄…………………………………………………………49-61
圖1、細胞模型…………………………………………………………49
圖2、細胞核局部損傷模型(Local damage model) ……………………50
圖3、蒙地卡羅方法應用在圓周率計算的示意圖……………………51
圖4、各種核種的光譜能量誘發造成的各種DNA損傷百分比……53
圖4.1、125I的各種光譜能量誘發造成的各種DNA損傷百分比………53
圖4.2、119Sb的各種光譜能量誘發造成的各種DNA損傷百分比……54
圖4.3、123I的各種光譜能量誘發造成的各種DNA損傷百分比………55
圖4.4、111In的各種光譜能量誘發造成的各種DNA損傷百分比………56
圖4.5、99mTc的各種光譜能量誘發造成的各種DNA損傷百分比………57圖5、利用MCDS模擬出電子能量為0.1keV到10keV之間，所造成的SSB以及DSB的產率………………………………………………58
圖6、各個發射鄂惹電子核種的SSB、DSB產率……………………59
圖7、各個發射鄂惹電子核種單位體積的的SSB、DSB產率………60
圖8、在RC=5μm、RN=2μm的情況下，不同的電子能量大小對應的細胞S值………………………………………………………………61
柒、表目錄……………………………………………………………62-77
表一、各個鄂惹電子發射體核種 (125I, 119Sb, 123I, 111In, and 99mTc) 的光譜………………………………………………………………………62
表二、不同粒子數以及不同電子能量模擬所需時間測定…………64
表三、使用不同粒子數利用Penelope code進行模擬後得到的細胞S值………………………………………………………………………65
表四、模擬在不同細胞核半徑情況下得到的細胞S值，並與Goddu et al 1997發表的資料進行比較…………………………………………66
表五、模擬在不同粒子數、不同半靜的情況下所得到的細胞S值，並與Goddu et al 1997發表的資料進行比較……………………………68
表六、模擬的結果與Bousis et al. 2010發表的資料進行比較………68
表七、模擬後各個核種(125I, 119Sb, 123I, 111In, and 99mTc)的細胞S值與過去已發佈的值進行比較………………………………………………69
表八、各個放射核種125I, 119Sb, 123I, 111In, and 99mTc 在半徑為4μm的細胞核中，所造成的單股螺旋斷裂(SSB)以及雙股螺旋斷裂(DSB)的產率………………………………………………………………………71
表九、各個放射核種125I、119Sb、123I、111In、與99mTc 在半徑為4μm的細胞核中，所造成各種不同形式的DNA損傷的產率值…………72
表十、將各個放射核種125I、119Sb、123I、111In、與99mTc模擬後得到的總DSB產率，以相對生物效應的方式進行比較……………………73
表十一，125I放出1.270x 10^-4MeV的鄂惹電子時，此能量造成不同型態DNA損傷的百分比分佈…………………………………………73
表十二、125I的鄂惹電子光譜各個能量時，造成的鹼基損傷的百分比………………………………………………………………………74
表十三、99mTc發出的低能電子(116eV與226eV)在細胞核半徑0.5μm到4.0μm之間的情況下，對於誘發造成DSB+、DSB++，佔所有光譜結果的百分比比較表…………………………………………………75
表十四、125I發出的低能電子(<1000eV)在細胞核半徑0.5μm到4.0μm之間的情況下，對於誘發造成DSB+、DSB++，佔所有光譜結果的百分比比較表……………………………………………………………76
表十五、125I與99mTc的低能電子平均能量…………………………77
表十六、將125I, 119Sb, 123I, 111I與 99mTc的各種DNA損傷形式，以99mTc做為基準進行相對生物效應(RBE)的比較……………………………77
捌、附表及附圖……………………………………………………78-80
附表一、各個放射核種125I、119Sb、123I、111In、99mTc的物理半衰期及其衰變模式……………………………………………………………78
附圖一、輻射線進入細胞後所產生的各種現象……………………78
附圖二、電子具備不同能量時，相對應的線性能量轉移以及距離…79
附圖三、DNA損傷的型態區分…………………………………………79
附圖四、鄂惹電子是藉由CKMMX 與Auger MXY放出時，與131I的β衰變以及211At放出的α粒子造成細胞致死與突變的情形…………80
附圖五、標誌藥物[125I] IUdR與[123I]IUdR對人類大腦膠質細胞UVW給藥後的實驗結果……………………………………………………80
玖、參考文獻……………………

Ager DD, Dewey WC, Gardiner K, Harvey W, Johnson RT,Waldren CA 1990 Measurement of radiation-induced DNA double-strand Breaks by pulsed-field gel electrophoresis Radiat Res.122 181-187

Baró J, Sempau J, Fernández-Varea JM and Salvat F 1995 PENELOPE: an algorithm for Monte Carlo simulation of the penetration and energy loss of electrons and positrons in matter Nucl. Instrum Methods Phys. Res. B 100 31-46

Belli M, Cherubini R, Dalla Vecchia M, Dini V, Moschini G, Signoretti C, Simone G, Tabocchini MA, Tiveron P. 2000 DNA DSB induction and rejoining in V79 cells irradiated with light ions: a constant field gel electrophoresis study Int J Radiat Biol. 76 1095-1104

Bernhardt P, Forssell-Aronsson E, Jacobsson L, Skarnemark,G 2001 Low-energy Electron Emitters for Targeted Radiotherapy of Small Tumours. J. Nucl. Med. 40 602-608

Bousis C, Emfietzoglou D, Hadjidoukas P, Nikjoo H 2010 Monte Carlo single-cell dosimetry of Auger-electron-emitting radionuclides. Phys. Med. Biol. 55 2555-2572

Boyd M, Ross SC, Dorrens J, Fullerton NE, Tan KW, Zalutsky MR, Mairs RJ 2006 Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and Auger electron–emitting radionuclides J. Nucl. Med. 47 1007-1015

Cai Z, Pignol JP, Chan C, Reilly RM 2010 Cellular dosimetry of 111In using Monte CarloN-particle computer code: comparison with analytic methods and correlation with in vitro cytotoxicity. J. Nucl. Med. 51 462-470

Capello A, Krenning EP, Breeman WAP, Bernard BF, Marion de Jong 2003 Peptide Receptor Radionuclide Therapy In Vitro Using [111In-DTPA0]Octreotide J. Nucl. Med. 44 98-104

Costantini DL, Chan C, Cai Z, Vallis KA, Reilly RM 111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer J. Nucl. Med. 48 1357-1368

Eckerman KF and Endo A 2008 MIRD: Radionuclide Data and Decay Sch emes. Reston, VA: Society of Nuclear Medicine

Eckhardt R 1987 Stan Ulam, John Von Neumann, and the Monte Carlo Method Los Alamos Science Special 131-141

Elmroth K, Stenerlo ̈w B 2005DNA-incorporated 125I induces more than one double strand break per decay in mammalian cells Radiat. Res.163 369-373

Faraggi M, Gardin I, Stievenart JL, Bok BD and Le Guludec D 1998 Comparison of cellular and conventional dosimetry in assessing self-dose and cross-dose delivered to the cell nucleus by electron emissions of 99mTc, 123I, 111In, 67Ga and 201Tl. Eur. J. Nucl. Med. 25 205-214

Farber JM. 1996 An introduction to the hows and whys of molecular typing J. Food Prot. 59 1091-1101

Ftácniková S, Böhm R 2000 Monte carlo calculations of energy deposition on cellular, multicellular and organ level for auger emitters Radiat Prot Dosimetry 92 279-288

Germain D, Gentilhomme O, Bryon P A and Coiffier B 1981 Cellules sanguines et organs he ́matopoi ̈e ́tiques Physiologie Humaine ed S A Simep (Villeurbanne: Simep SA) 184–247

Goddu SM, Howell RW, Rao DV 1994 Cellular dosimetry:absorbed fractions for monoenergetic electron and alpha particle sources and S-values for radionuclides uniformly distributed in different cell compartments J. Nucl. Med. 35 303-316

Goddu SM, Howell RW, Bouchet LG, Bolch WE, Rao DV 1997 MIRD cellular S Values: self-absorbed dose per unit cumulated activity for selected radionuclides and monoenergetic electron and alpha particle emitters incorporated into different cell compartments. Society of Nuclear Medicine.

Gudowsk-Nowak E, Ritter S,Taucher-scholz G, Kraft G 2000 Compound poisson processes and clustered damage of radiation induced DNA double strand breaks Acta physica polonica B 31 1109-1124

Howell RW 1992 Radiation spectra for Auger-electron-emitting radionuclides: report No. 2 of AAPM Nuclear Medicine Task Group No. 6. Med. Phys. 19 1371-1383

Howell RW 1994 The MIRD Schema: From Organ to Cellular Dimensions. J. Nucl. Med.35 531-533

Hsiao Y and Stewart RD 2008 Monte Carlo simulation of DNA damage induction by x-rays and selected radioisotopes. Phys. Med. Biol. 53 233-44

Humm JL and Charlton DE 1989 A new calculational method to assess the therapeutic potential of Auger electron emission. Int. J Radiat. Oncol. Biol. Phys. 17 351-360

Jackson SP 2002 Sensing and repairing DNA double-strand breaks Carcinogenesis 23 687-696

Janson ET, Westlin JE, O ̈hrvall Ulf, O ̈berg K, Lukinius A 2000 Nuclear Localization of 111In After Intravenous Injection of [111In-DTPA-D-Phe]-Octreotide in Patients with Neuroendocrine Tumors
J. Nucl. Med. 41 1514-1518

Kase Y, Kanai T, Matsufuji N, Furusawa Y, Elsässer T, Scholz M 2008 Biophysical calculation of cell survival probabilities using amorphous track structure models for heavy-ion irradiation. Physics in medicine and biology 53 37-59

Kassis AI 1982 Lethality of Auger Electrons from the Decay of Bromine-77 in the DNA of Mammalian Cells Radiat Res. 90 362-373

Kassis AI,Fayad F,Kinsey BM,Sastry KSR, Adelstein 1989 Radiotoxicity of an 1251-LabeledD NA Intercalator in Mammalian Cells Radiat Res.118 283-294

Kassis AI 2004 The amazing world of Auger electrons. Int. J. Radiat. Biol. 80 789-803

Kassis AI 2008 Therapeutic radionuclides : biophysical and radiobiologic principles. Semin. Nucl. Med. 38 358-366

Khanna KK, Jackson SP 2001DNA double-strand breaks: signaling,repair and the cancer connection Nature Genetics 27 247-254

Lobachevsky PN and Martin RF 2004 Plasmid DNA breakage by decay of DNA-associated Auger emitters: experiments with 123I/125I-iodoHoechst 33258. Int. J. Radiat. Biol. 80 915-920

Mackie TR 1990 Applications of the Monte Carlo Method in Radiotherapy The dosimetry of ionizing radiation volume III 541-620

Michel RB, Brechbiel MW, Mattes MJ 2003 A Comparison of 4 Radionuclides Conjugated to Antibodies for Single-Cell Kill J. Nucl. Med. 40 602-608

Neshasteh-Riz A, Mairs RJ, Angerson WJ, Stanton PD, Reeves JR, Rampling R, Owens J, Wheldon TE 1998 Differential cytotoxicity of [123I]IUdR, [125I]IUdR and [131I]IUdR to human glioma cells in monolayer or speroid culture: effect of proliferative heterogeneity and radiation cross-fire Br J Cancer. 77 385-390

Nikjoo H, O''Neill P, Goodhead DT, Terrissol M 1997 Computational modelling of low-energy electron-induced DNA damage by early physical and chemical events. Int. J. Radiat. Biol. 71 467-483

Nikjoo H, O''Neill P, Terrissol M, Goodhead DT 1999 Quantitative modelling of DNA damage using Monte Carlo track structure method. Radiat. Environ. Biophys.38 31-38

Nikjoo H, O''Neill P, Wilson WE, Goodhead DT 2001 Computational approach for determining the spectrum of DNA damage induced by ionizing radiation. Radiat Res. 156 577-583

Rogers DWO 2006 Fifty years of Monte Carlo simulations for medical physics Phys Med Biol.51 R287-R301

Scholz M, Kraft G 2004 The Physical and Radiobiological Basis of the Local Effect Model: A Response to the Commentary by R. Katz Radiat Res. 161 612-620

Salvat F,Ferna ́ndez-Varea JM, Sempau J 2011 PENELOPE-2011
A Code System for Monte Carlo Simulation of Electron and Photon Transport(version 2011) OECD NEA Data Bank/NSC DOC(2011)/5

Semenenko VA and Stewart RD 2004 A fast Monte Carlo algorithm to simulate the spectrum of DNA damages formed by ionizing radiation. Radiat. Res. 161 451-457

Semenenko VA and Stewart RD 2006 Fast Monte Carlo simulation of DNA damage formed by electrons and light ions. Phys. Med. Biol. 51 1693-1706

Sempau J,Acosta E,Bar ̀o J, Ferna ́ndez-Varea JM, Salvat F 1997 An algorithm for Monte Carlo simulation of coupled electron-photon transport Nuclear Instruments and Methods in Physics Research Section B 132 377-390


Stewart RD, Wilson WE, McDonald JC and Strom DJ 2002 Microdosimetric properties of ionizing electrons in water: a test of the PENELOPE code system. Phys. Med. Biol. 47 79-88

Tavares AA and Tavares JM 2010 Evaluating 99mTc Auger electrons for targeted tumor radiotherapy by computational methods. Med Phys. 37 3551-3559

Tenover FC, Arbeit RD, Goering RV, Mickelsen PA, Murray BE, Persing DH, Swaminathan B.1995 Interpreting chromosomal DNA restriction patterns by pulsed-field gel electrophoresis: criteria for bacterial strain typing J Clin Microbiol 33 2233-2239

Terrissol M, Peudon A, Kummerle E and Pomplun E 2008 On the biological efficiency of I-123 and I-125 decay on the molecular level. Int. J. Radiat. Biol. 84 1063-1068

Van den Heuvel F, Locquet JP and Nuyts S 2010 Beam energy considerations for gold nano-particle enhanced radiation treatment Phys. Med. Biol. 55 4509-20

Walicka MA,Adelstein SJ,Kassis AI 1998 Indirect mechanisms contribute to biological effects produced by decay of DNA-incorporated Iodine-125 in mammalian cells in vitro: Double strand breaks Radiat. Res.149 134-141

Xue LY, Butler NJ, Makrigiorgos GM, Adelstein SJ and Kassis AI 2002 Bystander effect produced by radiolabeled tumor cells in vivo. Proc. Natl. Acad. Sci. USA 99 13765-13770

Yasui LS, Hughes A, DeSomber ER 2001 Relative Biological Effectiveness of Accumulated 125IdU and 125I-Estrogen Decays in Estrogen Receptor-Expressing MCF-7 Human Breast Cancer Cells Radiat. Res.155 328-334

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