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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林亮音 | |
dc.contributor.author | Wen-Chun Chen | en |
dc.contributor.author | 陳玟君 | zh_TW |
dc.date.accessioned | 2021-06-15T11:42:52Z | - |
dc.date.available | 2021-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-15 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49701 | - |
dc.description.abstract | 急性骨髓性白血病(Acute myeloid leukemia, AML)是一個異質性高的血液惡性疾病,其中一種常見的基因變異為FLT3內部串聯重複(FLT3-ITD),此變異在所有AML病人中佔了大約20~25%,並且已知和不良預後有關,也增加化學治療後復發的風險。目前已發展出許多針對FLT3蛋白的標靶藥物,但病人於治療後產生抗藥性是標靶藥物在臨床上所面臨的難題,因此有必要了解AML對小分子藥物的抗藥機制以及找尋克服抗藥性的治療策略。
本實驗室先前的研究發現酪胺酸激酶抑制劑cabozantinib於低劑量得以抑制具有FLT3-ITD突變的AML細胞生長,而為了探討cabozantinib在臨床上可能面臨的抗藥性問題,本研究利用AML細胞株MV4-11建立出對cabozantinib抗藥的細胞株MV4-11-XR,此抗藥株對cabozantinib的IC50為1504.6 ± 228.6 nM,而母株為9.5 ± 2.3 nM。 進一步分析MV4-11-XR細胞中FLT3 cDNA序列,結果發現兩種轉錄產物:FLT3-ITD/D835Y及FLT3-ITD/Exon 20。使用pyrosequencing及GeneScan的方法確認此兩種突變是從MV4-11細胞中篩選出來的結果。另外以西方墨點法分析FLT3及其下游訊息傳遞路徑的蛋白表現,除了p-FLT3及t-FLT3在抗藥株的表現較母株增加外,p-STAT5及p-AKT的表現也都上升,只有p-ERK沒有變化。此外,抗凋亡蛋白Mcl-1以及抑癌蛋白p53亦較母株細胞表現高。延伸探討p53蛋白表現量上升的情況,發現TP53基因變異由異型合子轉變成同型合子的突變,使得p53蛋白皆產生R248W突變而失去正常功能。 另外,以細胞抑殺實驗檢測其他酪胺酸激酶抑制劑對MV4-11-XR抗藥株之生長抑制情形,結果顯示抗藥株對crenolanib及midostaurin具有較佳的感受性,相對地,對sorafenib與quizartinib的感受性較差。以MEK抑制劑CI-1040,AKT抑制劑MK-2206處理MV4-11-XR抗藥株,無法在臨床上可達的藥物濃度下,達到抑制效果。而已知rRNA轉錄的增加和腫瘤生成有關聯,使用抑制rRNA轉錄的RNA polymerase I抑制劑CX-5461處理MV4-11-XR,能有效於低藥物濃度抑制MV4-11-XR細胞的生長。 總體而言,實驗室建立出來的MV4-11-XR細胞確實對Cabozantinib產生抗藥性。從我們的實驗結果顯示FLT3-ITD/D835Y及FLT3-ITD/Exon 20突變伴隨FLT3及其下游訊息傳遞路徑的蛋白表現量增加和Mcl-1蛋白過度表現與p53之R248W同型合子突變,是造成MV4-11-XR細胞對Cabozantinib產生抗藥性的可能原因。 | zh_TW |
dc.description.provenance | Made available in DSpace on 2021-06-15T11:42:52Z (GMT). No. of bitstreams: 1 ntu-105-R03424012-1.pdf: 3442948 bytes, checksum: 656b8ab86e74afa1ee7887ac92582755 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 目錄....................................................................................................................................I
圖目錄.............................................................................................................................IV 表目錄..............................................................................................................................V 縮寫表.............................................................................................................................VI 摘要................................................................................................................................VII Abstract......................................................................................................................... IX 第一章 前言...................................................................................................................1 1.1. 急性骨髓性白血病........................................................................................1 1.1.1. 急性骨髓性白血病之分類..................................................................1 1.1.2. 急性骨髓性白血病之治療..................................................................1 1.2. FLT3激酶......................................................................................................2 1.3. 酪胺酸激酶抑制劑(tyrosine kinase inhibitor, TKI) .....................................3 1.3.1. Cabozantinib (XL-184)之簡介............................................................4 1.3.2. 酪胺酸激酶抑制劑之抗藥性..............................................................5 1.4. RNA聚合酶I抑制劑...................................................................................5 1.5. Mcl-1蛋白之簡介.........................................................................................6 1.6. p53蛋白之簡介.............................................................................................6 1.7. 多重抗藥性與ABC傳輸蛋白......................................................................7 第二章 研究目的...........................................................................................................8 第三章 材料與方法.......................................................................................................9 3.1. 材料................................................................................................................9 3.1.1. 細胞......................................................................................................9 3.1.2. 儀器設備..............................................................................................9 3.1.3. 藥品....................................................................................................10 3.1.4. 抗體....................................................................................................12 3.1.5. 試劑組................................................................................................12 3.1.6. 藥品與試劑配置................................................................................13 3.2. 方法..............................................................................................................14 3.2.1. 細胞培養............................................................................................14 3.2.2. 細胞抑殺試驗 (MTS assay) ............................................................15 3.2.3. 細胞生長曲線....................................................................................15 3.2.4. 細胞型態觀察....................................................................................15 3.2.5. 白血球表面抗體螢光染色................................................................15 3.2.6. 細胞萃取物製備................................................................................16 3.2.7. 蛋白質定量........................................................................................16 3.2.8. 西方墨點法 (Western blot analysis) ................................................16 3.2.9. DNA萃取..........................................................................................17 3.2.10. RNA萃取...........................................................................................17 3.2.11. 反轉錄聚合酶連鎖反應 (RT-PCR) ................................................18 3.2.12. 聚合酶連鎖反應 (PCR) ..................................................................19 3.2.13. 電泳分析...........................................................................................19 3.2.14. 聚合酶連鎖反應產物純化...............................................................19 3.2.15. 序列分析...........................................................................................20 3.2.16. 即時監控聚合酶連鎖反應 (Real-time PCR) .................................20 3.2.17. Pyrosequencing...................................................................................21 3.2.18. GeneScan............................................................................................21 3.2.19. 對Cabozantinib有抗藥性的細胞之建立........................................22 3.2.20. 單顆細胞分離(single cell isolation) ................................................22 3.2.21. 統計方法...........................................................................................22 第四章 實驗結果.........................................................................................................23 4.1. 建立對Cabozantinib抗藥的MV4-11細胞株—MV4-11-XR....................23 4.2. MV4-11-XR細胞株之FLT3 cDNA序列分析...........................................23 4.3. 從抗藥細胞株中挑選單顆細胞株進行分析..............................................24 4.4. MV4-11-XR細胞株之FLT3 DNA序列分析.............................................24 4.5. MV4-11-XR細胞株之型態觀察、表面抗原及生長狀況.........................25 4.6. MV4-11-XR細胞株之FLT3及其訊息傳遞下游分子的活化情形..........25 4.7. MV4-11-XR細胞株之抑癌蛋白與抗凋亡蛋白的表現情形.....................25 4.8. MV4-11-XR細胞株之多重抗藥性相關基因的表現情形.........................26 4.9. MV4-11-XR細胞株之單一藥物治療的抑制效果.....................................26 4.10. MV4-11-XR細胞株之合併藥物治療的抑制效果...................................27 第五章 討論.................................................................................................................29 第六章 參考文獻.........................................................................................................34 圖.....................................................................................................................................44 附圖.................................................................................................................................60 表.....................................................................................................................................64 附表.................................................................................................................................66 | |
dc.language.iso | zh-TW | |
dc.title | Cabozantinib抗藥性血癌細胞株MV4-11-XR的建立、特性研究及其治療策略 | zh_TW |
dc.title | Establishment, characterization and treatment strategy of cabozantinib-resistant MV4-11-XR leukemic cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 胡忠怡,郭遠燁,歐大諒,顧雅真 | |
dc.subject.keyword | 急性骨髓性白血病,FLT3-ITD/D835Y,cabozantinib抗藥性,MV4-11, | zh_TW |
dc.subject.keyword | AML,FLT3-ITD/D835Y,cabozantinib-resistance,MV4-11, | en |
dc.relation.page | 67 | |
dc.identifier.doi | 10.6342/NTU201602700 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-08-15 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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