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系統識別號 U0026-0812200914313279
論文名稱(中文) 纖維肉瘤合併處理放射線與三氧化二砷的細胞毒性機制探討
論文名稱(英文) Study on the cytotoxic mechanism of irradiation combined with arsenic trioxide in fibrosarcoma
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 96
學期 2
出版年 97
研究生(中文) 林靖華
研究生(英文) Jing-hua Lin
電子信箱 s7695408@mail.ncku.edu.tw
學號 s7695408
學位類別 碩士
語文別 中文
論文頁數 63頁
口試委員 指導教授-王應然
口試委員-郭靜娟
口試委員-潘敏雄
口試委員-何元順
中文關鍵字 G2/M期停滯  細胞凋亡  自體吞噬  放射線治療  三氧化二砷 
英文關鍵字 Radiotherapy  Arsenic trioxide  Autophagy  Apoptosis  G2/M arrest 
學科別分類
中文摘要 纖維肉瘤是軟組織肉瘤的一種,無論是以放射線治療或化學藥物治療,都發現癌細胞會對這些治療方式產生抗性,因此纖維肉瘤的癒後情況不良。放射線合併化學治療的方法是目前臨床上常見的惡性腫瘤治療模式,以提高癌症病人的存活率與病情控制。放射線治療可以誘使細胞產生不同的細胞反應,包括誘發DNA的傷害及G2/M期停滯。而化學治療藥物三氧化二砷(arsenic trioxide, As2O3)可以藉由促進細胞凋亡、誘使細胞分化或是抑制細胞增生與血管新生來達到治療癌症的功效。本篇研究最主要的目的在探討當合併放射線與三氧化二砷治療時,是否會增加對纖維肉瘤HT1080細胞的毒性並進一步探討其作用機制。在細胞實驗中,利用trypan blue來計算細胞存活率;使用流式細胞儀分析細胞週期、活性氧化物含量、粒線體膜電位的變化,及藉由annexin V-FITC分析早期細胞凋亡現象;DNA ladder則用來分析DNA的片段化;利用acridine orange染色觀察自體吞噬的酸性小泡(AVOs)產生;Western blotting則用來探討細胞凋亡與自體吞噬相關蛋白的表現;最後,並利用腫瘤異種移植之活體動物模式來探討放射線合併三氧化二砷的治療效果。結果指出,合併治療模式不論二者同時處理(co-treat)與先處理放射線後再加入三氧化二砷(post-treat)的方式,都比單獨處理放射線或三氧化二砷的效果好,包括降低細胞存活率及粒線體膜電位,增加細胞週期G2/M期的停滯、ROS的產生、以及早期細胞凋亡和自體吞噬百分比。在蛋白質表現量方面,合併治療可以增加p53、p21、p-cdc2、cyclin B1、p-cdc25c、LC3的表現,p-ERK、Bax、Hsp70及PARP的表現也有些微增加,cdc25c、bcl-2的表現量則是下降的趨勢,cyclin A、cdc2、Akt、p-Akt等蛋白沒有明顯改變。動物實驗中則發現,相較於單獨處理三氧化二砷與放射線的組別,合併處理可以有效抑制腫瘤的生長。此研究證明,三氧化二砷和放射線的合併治療能使具有抗性的HT1080細胞株死亡,達到癌症治療的效果,而其所誘發的死亡方式則包含了細胞凋亡及自體吞噬。
英文摘要 Fibrosarcoma is one of soft tissue sracoma which is resistance to radiotherapy and chemotherapy, and the prognosis is extremely poor. Currently, combined chemotherapy and radiotherapy has been shown in clinical to produced an improved survival and an improved disease control for cancer patients. Irradiation (IR) is thought to kill cells by causing DNA damage and inducing G2/M arrest. The anti-cancer effects of arsenic trioxide (ATO), a chemotherapeutic agent, has been attributed to the induction of apoptosis, inhibition of proliferation and angiogenesis, and promotion of differentiation. The major propose of this study is to investigate the cytotoxic mechanism of irradiation combined with arsenic trioxide in the treatment of fibrosarcoma HT1080 cells. In in vitro study, cell viability was detected by trypan blue. Cell cycle distribution, ROS, membrane potential and early apoptosis with annexin V-FITC apoptosis detection kit was analyzed by flow cytometry. DNA fragmentation was detected by agarose gel electrophoresis. In order to observe the expression of acidic vesicular organelle (AVOs) which is characteristic of autophagy; cells were stained with acridine orange. Western blotting was performed to analysis the expression of protein related to apoptosis and autophagy. In in vivo study, therapeutic efficacy of ATO and IR in HT1080 cells xenografts after treatment was assessed. Our results indicated the combination of IR and ATO was shown to be significantly more active than either treatment alone in two combination sequences comcomitant treatment, or sequential treatment with IR followed by ATO in HT1080 cells. Combined treatment decreased cell viability, caused membrane potential damage, and cell cycle G2/M arrest. They also increased the persentage of intracellular ROS, apoptosis and autophagy. The expression level of p53, p21, p-cdc2, cyclin B1, p-cdc25c and LC3 was increased significantly, however, p-ERK, Bax, Hsp70 and PARP were increased slightly. Decrement of cdc25c and bcl-2 expression was observed. Otherwise, no significantly change was found in the expression of cyclin A, cdc2, Akt and p-Akt. In in vivo study, combined treatment with IR and ATO inhibited tumor growth significantly than either treated alone. Taken together, this study demonstrated that IR combined with ATO may increase therapeuic efficacy of HT1080 cells. The cell death mechanisms induced by this combined treatment include apoptosis and autophagy.
論文目次 壹、序 論 1
貳、文獻回顧 2
第一節 軟組織肉瘤及治療策略 2
第二節 人類纖維肉瘤及其治療 2
第三節 放射線治療 4
第四節 化學治療法 5
第五節 三氧化二砷與其醫療用途 5
第六節 放射線合併化學治療 8
第七節 細胞週期與放射線敏感性 9
第八節 細胞凋亡(Apoptosis)與自體吞噬(Autophagy) 10
?、研究目的 13
肆、研究架構 14
伍、研究材料與方法 16
研究材料
(一) 細胞株 16
(二) 儀器 16
(三) 試劑 17
(四) 溶液 18
研究方法
(一) 細胞培養 19
(二) 細胞解凍 20
(三) 細胞繼代培養 20
(四) 細胞冷凍 20
(五) 細胞計數 21
(六) 細胞週期分析 21
(七) 活性氧物種(ROS)分析 22
(八) 粒線體膜電位分析 22
(九) 細胞凋亡分析 22
(十) 自體吞噬(細胞自噬)分析 23
(十一) DNA ladder Analysis 23
(十二) Acridine orange免疫螢光染色 24
(十三) Western blotting 24
(十四) BALB/c nu/nu mice腫瘤誘發實驗 27
(十五) 統計分析 28
陸、實驗結果 30
第一節 放射線和三氧化二砷對HT1080細胞的劑量及時間效應 30
第二節 放射線合併三氧化二砷對HT1080細胞的細胞週期變化 31
第三節 探討放射線與三氧化二砷對HT1080細胞凋亡現象 32
第四節 分析HT1080細胞Autophagy的表現 33
第五節 細胞訊息傳遞路徑之相關蛋白表現 34
第六節 腫瘤異種移植活體動物模式 35
柒、討 論 36
捌、結論與建議 40
玖、參考文獻 41
圖表 51
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