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研究生:溫欣儀
研究生(外文):Wen, Hsin-Yi
論文名稱:帝盟多合併咖啡因對於神經膠質瘤的抗腫瘤作用
論文名稱(外文):Synergistic Anti-tumor Effect of Temozolomide and Caffeine on Glioma.
指導教授:戴建國戴建國引用關係
指導教授(外文):Tai, Chien-Kuo
口試委員:黃憲斌、陳金城
口試委員(外文):Huang, Hsien-Bin、Chen, Jin-Cherng
口試日期:2017-07-18
學位類別:碩士
校院名稱:國立中正大學
系所名稱:生命科學系生物醫學研究所
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:2017
畢業學年度:105
語文別:中文
論文頁數:77
中文關鍵詞:神經膠質瘤帝盟多咖啡因
外文關鍵詞:GliomaTemozolomideCaffeine
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多形性膠質母細胞瘤(Glioblastoma multiforme, GBM)是成人中最常見的原發性惡性腦腫瘤,約佔50 %。世界衛生組織將GBM歸類為第Ⅳ級是最惡性預後最差的惡性腦腫瘤。目前常規的治療為手術切除後合併放射線治療與帝盟多(Temozolomide, TMZ)的化學治療,但預後相當不好,治療後平均存活14-15個月,並且容易有放化療的耐藥性產生。因此,尋求更好的治療方式就更加的重要,目前研究趨勢大多以TMZ合併其他藥物的方式來增加治療效果。有研究指出咖啡因能抑制鈣離子釋放通道阻斷GBM侵襲並延長存活率;且能抑制神經膠質瘤細胞的增殖並增加經由caspase 3導致的細胞凋亡。另外,咖啡因也可抑制DNA損傷檢查點、防止因DNA損傷所誘導的γ-H2AX聚集與同源重組及抑制細胞產生保護性自噬作用,避免耐藥性的產生。目前咖啡因對於腦瘤的研究並不多見,且機制與效果還在釐清。因此,本實驗預計探討TMZ合併咖啡因對於神經膠質瘤的治療效果,來評估合併用藥對於抗腫瘤的療效。實驗方法:以RT2細胞分別處理不同濃度TMZ與咖啡因後進行細胞存活、增殖與遷移實驗。並在大鼠皮下植入RT2細胞使其形成腫瘤,再口服給予藥物:A組為對照組,不接受任何治療;B組口服帝盟多(30 mg/kg);C組同時口服帝盟多與咖啡因(100 mg/kg)。實驗結果顯示RT2細胞為MGMT高表現的細胞並且對於TMZ有耐藥性,而合併用藥明顯降低細胞存活、增殖與遷移,並且對於皮下腫瘤確實有明顯的抑制作用,能降低CHOP、增加cleaved caspase 3及LC3A/B的蛋白質表現。目前研究結果對於治療GBM有很大的幫助,未來預計進行顱內腫瘤實驗,希望能更直接的了解並控制腫瘤的生長和侵襲行為及細胞和分子機制以提供新的治療方法。
Glioblastoma multiforme (GBM) is the most common adult primary brain tumor, accounting for 50 % of all brain tumors. WHO classified as a grade IV, GBM are the most poor prognosis malignant brain tumors. Current standard includes after surgery combined with adjuvant radiotherapy or chemotherapy using temozolomide (TMZ), but after treatment the survival still only 14-15 month and appear chemoradiotherapy resistance leading to tumor recurrence. Current approaches often suggest combination of TMZ with other agents to increase efficacy for GBM treatment. Previously studies shown caffeine-mediated inhibition of calcium release channel blocks GBM invasion and extends survival, and inhibits cell proliferation, increase caspase-dependent apoptosis of glioma cells. Caffeine can efficiently inhibit the DNA damage checkpoint and prevent DNA damage induced γ-H2AX enrichment, and inhibition of homologous recombination and autophagy. However, the effects of combined caffeine and TMZ on glioma were still unclear. In this study, we aimed to investigate the efficacy of TMZ and caffeine on malignant glioma in rats. Study methods: The cell viability, colony formation, and wound healing assay of RT2 cells under the treatment of caffeine and/or TMZ. RT2 glioma cells were implanted into the subcutaneous space in Fischer 344 rats. Group A was control group; group B was TMZ (30 mg/kg); group C was TMZ plus caffeine (100 mg/kg); oral administration. The results showed that combination therapy had greater efficacy against glioma cell lines and was significantly reduced cell survival, proliferation and migration, subcutaneous tumor has a significant inhibitory effect, reduce CHOP, increase the cleaved caspase 3 and LC3A/B protein expression. The results of this study have a great deal of help in the treatment of GBM. In the future, intracranial tumor experiments were performed to better understanding and control glioma growth and transmission of cellular and molecular processes that provide new treatments.
中文摘要.Ⅰ
Abstract.Ⅲ
目錄.Ⅴ
圖表目錄.Ⅶ
1.前言與背景.1
1.1 腦瘤.1
1.2 血腦屏障(Blood brain barrier, BBB)介紹.3
1.3 帝盟多(Temozolomide, TMZ)介紹.5
1.4 惡性腦腫瘤的抗藥機制.6
1.5 咖啡因(Caffeine)介紹.8
1.6 動機.10
2.材料方法.12
2.1 細胞株與細胞培養.12
2.2 西方墨點法(Western Blot).13
2.3 細胞存活試驗(Cell Viability).14
2.4 細胞群落形成分析(Colony Formation Assay).15
2.5 細胞遷移能力分析(Wound Scratch Assay).16
2.6 In vivo皮下腫瘤之植入.17
2.7 載體轉染(Transfection).17
2.8 病毒載體感染細胞(Infection).18
2.9 In vivo顱內腫瘤之建立.19
2.10 腫瘤螢光訊號測試.19
2.11 統計分析.20
3.結果.21
3.1 不同細胞株之MGMT蛋白質表現.21
3.2 單獨與合併用藥抑制細胞存活的效率.21
3.3 單獨與合併用藥抑制細胞增殖的效率.23
3.4 單獨與合併用藥抑制細胞遷移的效率.24
3.5 合併用藥對於大鼠皮下腫瘤的治療效果.27
3.6 皮下腫瘤之各項蛋白質表現.28
3.7 慢病毒感染RT2細胞.29
3.8 大鼠腦內腫瘤生長情形.29
4.討論.30
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