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系統識別號 U0026-2108201800330300
論文名稱(中文) 探討化療藥物氨甲蝶呤在乳腺癌體外以及原部位腫瘤動物模式中對於細胞毒性及放射線增敏性之影響
論文名稱(英文) Investigate the cytotoxic and radiosensitizing effects of Methotrexate on breast cancer cell in vitro and in orthotopic mouse model in vivo
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 106
學期 2
出版年 107
研究生(中文) 李珮綺
研究生(英文) Pei-Chi Li
學號 S76044086
學位類別 碩士
語文別 中文
論文頁數 100頁
口試委員 指導教授-王應然
口試委員-吳沅樺
口試委員-何聖佑
口試委員-邱惠雯
中文關鍵字 乳癌  放射線治療  氨甲蝶呤  細胞自體吞噬  細胞凋亡 
英文關鍵字 breast cancer  ionizing radiation (IR)  methotrexate  autophagy  apoptosis 
學科別分類
中文摘要 乳癌不論是在全世界或台灣,一直是女性癌症發生率的第一名,雖然現在醫療進步,提早發現治療,五年存活率很高,但也由於現代人生活型態的改變,造成罹癌風險大大的增加,其中三重陰性乳癌(Triple -negative breast cancer,TNBC)又為乳癌類型中最難治療、復發轉移率也最高的一種,因此關於TNBC的更多治療策略研究是必須的,而透過合併療法,能夠透過化療藥物不同的分子機制增加毒殺效果並降低抗藥性跟副作用、使重疊的毒性最小化,其中放射線為臨床上常常作為輔助性治療的方法,但其不可避免的會對正常組織造成一定的傷害,或有明顯的副作用出現,因此合併的療法為可以降低放射線劑量卻不影響療效的權衡辦法,而由於乳癌細胞有高表達的葉酸,我們以合併使用葉酸的結抗劑-氨甲蝶呤以及放射線為策略來治療乳癌,藉由體外試驗以及原部位乳腺癌小鼠動物模式,探討氨甲蝶呤(Methotrexate)合併處理放射線是否對乳腺癌細胞具有協同毒殺效果,並了解其誘發的細胞死亡模式以及自體吞噬所扮演的角色。在體外試驗,分別以單獨處理放射線、氨甲蝶呤(Methotrexate)以及合併處理小鼠三陰性乳腺癌細胞株4T1-Luc,使用Trypan blue exclusion assay分析細胞毒殺效果並用劑量效應分析軟體計算其combination index(CI)值分析協同效果;利用流式細胞儀測定細胞死亡模式及細胞週期變化;透過西方墨點法及免疫螢光染色分析細胞自體吞噬情形;而由於透過標記的方式達到更專一效果是現今一個很熱門的抗癌發展方向,因此我們也藉由西方墨點法探討其毒殺效果與steroid receptor coactivator-3(SRC-3)和6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4)之間的關係,期許未來能將SRC-3當作標的,也利用氨甲蝶呤(Methotrexate)辨識葉酸的能力達到更有效抑制乳腺癌細胞生長的作用。在動物實驗方面,建立原部位乳腺癌小鼠動物模式,並利用活體分子影像系統定時監測腫瘤的生長,於犧牲後取出腫瘤進行秤重觀察其治療效果。綜合細胞以及動物的實驗結果,相較於單獨處理組別,合併處理氨甲蝶呤(Methotrexate)與放射線能協同增強細胞毒殺效果並有效抑制腫瘤生長。為釐清協同效果的作用機制,在透過群落分析確認氨甲蝶呤(Methotrexate)的確可以增加放射線敏感性後,利用流式細胞儀分析細胞死亡模式,發現在處理24小時後,細胞凋亡及壞死在單獨以及合併的組別均沒有太多的表現;自體吞噬百分比在合併的組別確實比起單獨處理時明顯的增加,在加入自體吞噬抑制劑後,細胞存活率有回復的情形且細胞凋亡有增加的趨勢,表示細胞自體吞噬同時具有保護與毒殺的作用,而大部分扮演著促進死亡的角色。而SRC-3及PFKFB4、p-mTOR及p-Akt蛋白在合併處理後均有明顯得減少,綜合以上結果得知,合併處理氨甲蝶呤(Methotrexate)與放射線可能經由減少乳腺癌細胞SRC-3的表達,進而抑制Akt/mTOR及下游路徑並增加對乳腺癌細胞之抗癌效果。
英文摘要 Breast cancer is the most common cancer in women. Although the death rate has dropped recent years, the incidence is increasing because of the change of modern life style. There are several treatments for breast cancer, but problems still exist due to serious side effects triggered by clinical drugs and less anti-cancer activity in triple negative breast cancer. In this study, triple negative breast cancer cell line 4T1-Luc was applied to investigate the anti-cancer effects of ionizing radiation (IR) alone, folate receptors’ antagonist, methotrexate alone or in combination and to determine the mechanisms of these effects in vitro and in vivo. In our current results, we confirm that methotrexate did replace the site of folate receptors which highly express in breast cancer cell and have cytotoxic effect, combined treatment increased the therapeutic efficacy which resulted in a synergistic effect also induced remarkable autophagy, type II programmed cell death in breast cancer cell line, apparent apoptosis and necrosis through long time period. Furthermore, we focus on a novel target SRC-3, which over express in breast cancer cell line. We suggest that the metabolic enzyme PFKFB4 down regulate the high expression level of SRC-3 and was significantly decreased in 4T1-Luc cells treated with combined treatment. In conclusion, our results demonstrated that the combination of methotrexate and radiation exerts strong cytotoxic effects in breast cancer and deserve further clinical-related investigation.
論文目次 目錄

第一章、序論 15
第二章、文獻回顧 16
第一節、乳癌(Breasr cancer) 16
第二節、氨甲蝶呤(Methotrexate, MTX) 18
第三節、乳腺癌細胞葉酸受體表達與胰臟癌細胞比較 20
第四節、合併放射線療法(Combine radiation treatment) 21
第五節、細胞凋亡、細胞壞死與自體吞噬(Apoptosis, Necrosis and Autophagy) 23
第六節、細胞週期(Cell cycle) 25
第七節、Steroid receptor coactivator 3 (SRC-3)和6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) 28
第八節、原部位移植小鼠動物模式(Orthotopic In vivo mouse model) 29
第三章、研究目的 31
第四章、研究材料與方法 32
第一節 研究材料 32
(一) 細胞株 32
(二) 儀器 32
(三)試劑與耗材 34
第二節、研究方法與實驗步驟 38
一、細胞培養 (Cell culture) 38
二、細胞解凍 38
三、細胞冷凍 38
四、細胞存活率 (Cell viability) 38
五、協同效應分析 (Synergistic interaction) 39
六、細胞群落分析 (Clonogenic assay) 39
七、早期細胞凋亡分析 (Early apoptosis) 39
八、早期細胞凋亡、晚期細胞凋亡及細胞壞死分析 39
九、自體吞噬Acridine orange(AO) 分析 40
十、免疫螢光染色 (Immunofluorescence) 40
十一、西方墨點法 (Western blotting) 40
十二、Stable transfection (Luciferase) 42
十三、原位癌乳腺癌小鼠動物模式 (Orthotopic In vivo mouse model) 42
第五章、研究架構 44
第六章、實驗結果 47
第一節、放射線和氨甲蝶呤Methotrexate對4T1乳腺癌細胞的毒性劑量效應 47
第二節、放射線合併氨甲蝶呤Methotrexate對於MiaPaCa-2胰臟癌細胞株與4T1乳腺癌細胞株之毒性效果比較 47
第三節、探討氨甲蝶呤Methotrexate是否能夠增加4T1小鼠乳腺癌細胞對於放射線敏感性. 48
第四節、分析合併處理放射線與氨甲蝶呤Methotrexate影響4T1小鼠乳腺癌細胞之細胞凋亡、細胞壞死與自體吞噬的變化 49
第五節、探討合併處理放射線合併氨甲蝶呤Methotrexate對4T1小鼠乳腺癌細胞誘發自體吞噬現象 51
第六節、放射線合併氨甲蝶呤Methotrexate對4T1小鼠乳癌細胞之細胞週期影響 52
第七節、探討放射線合併氨甲蝶呤Methotrexate對4T1小鼠乳癌細胞之長時間細胞存活率以及死亡模式 52
第八節、Steroid receptor coactivator 3 (SRC-3)和6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) 53
第九節、乳腺癌原部位腫瘤小鼠動物模式 54
第七章、討論 56
第八章、結論及建議 63
第九章、參考文獻 64


圖目錄

圖一、女性乳癌分期示意圖 18
圖二、女性乳房解剖圖 18
圖三、葉酸及氨甲蝶呤結構圖 20
圖四、DNA斷裂修復途徑 22
圖五、游離輻射損傷途徑 23
圖六、細胞凋亡的訊息傳遞路徑 25
圖七、細胞自體吞噬的過程示意圖 25
圖八、細胞週期與調控相關蛋白示意圖 27
圖九、SRC-3參與許多癌症相關途徑 29
圖十、胰臟癌原位動物模式 62
Fig. 1. Synergistic effects of Methotrexate and IR on 4T1 breast cancer cells. 75
Fig. 2. Comparing cytotoxicity of Methotrexate on MiaPaCa-2 pancreatic cancer cells and 4T1 breast cancer cells. 76
Fig. 3. Synergistic effects of Methotrexate and IR on MiaPaCa-2 pancreatic cancer cells. 77
Fig. 4. IR dose-response survival curves resulting from Methotrexate and/or IR treatment in breast cancer 4T1-Luc cells. 78
Fig. 5. Measurement of apoptosis in breast cancer 4T1-Luc cells receiving various treatments. 79
Fig. 6. Measurement of different cell death in 4T1-Luc cells receiving various treatments. 80
Fig. 7. Measurement of autophagy in breast cancer 4T1-Luc cells receiving various treatments. 83
Fig. 8. The role of autophagy in the treatment of 4T1-Luc cells with IR and Methotrexate. 84
Fig. 9. Cell cycle distribution of Methotrexate and IR treated alone or in combination in 4T1-Luc cells. 87
Fig. 10. Long time period detection of cell death of Methotrexate and IR treated alone or in combination in 4T1-Luc cells. 90
Fig. 11. Long time period detection of autophagy of Methotrexate and IR treated alone or in combination in 4T1-Luc cells. 91
Fig. 12. Investigate basal SRC-3 and measured expression of SRC-3 and PFKFB4 in breast cancer 4T1-Luc cells receiving various treatments. 92
Fig. 13. Combined treatment inhibits growth of 4T1-Luc cells in BALB/c mice treated with IR (4Gy) or MTX (6 mg/kg X 8) alone or in combination. 93
Supplemental Figure S1. The role of autophagy in the treatment of 4T1-Luc breast cancer cells with IR and Methotrexate alone or in combination for 48 hrs. 95
Supplemental Figure S2. The cell viability of 4T1-Luc breast cancer cells treated with IR and Methotrexate alone or in combination for 48, 72, 96 hrs. 96
Supplemental Figure S3. Characterization of Ag NPs. 97
Supplemental Figure S4. Confirmed the Enhanced permeability and retention (EPR) effects of nanosilver in NOD/SCID mice. 99


表目錄

Table 1. Biochemistry tests including GOT, GPT, Albumin, BUN, and Creatinine. 94
Supplemental Table.1. Physicochemical properties of AgNPs. 100


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