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研究生:洪子翔
研究生(外文):Tzu-Hsiang Hung
論文名稱:利用快速蒙地卡羅演算法計算鄂惹電子發射體誘發的DNA損傷
論文名稱(外文):Fast Monte Carlo simulation of DNA damage induced by Auger-electron emission
指導教授:蕭雅云蕭雅云引用關係
指導教授(外文):Ya-yun Hsiao
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:生物醫學科學學系碩士班
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:86
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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……………………

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魏群,崔麗華,楊淑杰,馬晴,姜國華,向本瓊,劉玉 分子生物實驗手冊 初版27-35台北 九州圖書文物有限公司


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