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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 林亮音(Liang-In Lin) | |
dc.contributor.author | Heng-An Liao | en |
dc.contributor.author | 廖珩安 | zh_TW |
dc.date.accessioned | 2021-06-08T00:43:50Z | - |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-11 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17804 | - |
dc.description.abstract | FLT3-ITD internal tandem duplication (ITD) mutations occur in 30% of acute myeloid leukemia (AML) patients. In clinical studies, patients with FLT3-ITD mutation are associated with adverse prognosis, and hence FLT3 is considered to be a potential target for AML therapies. Many FLT3 inhibitors have been developed and are undergoing clinical investigation. However, emerging of drug resistance after treatment has become an obstacle for full recovery. Development of new FLT3 inhibitors is urgently needed for better therapeutic strategies. Cabozantinib is a multikinase inhibitor that targets MET, VEGFR2, RET, KIT, TIE-2, and FLT3. It was found to be selectively cytotoxic to AML cells harboring FLT3-ITD in previous study. By using MTS assay and western blot analysis, we first confirmed the selective cytotoxicity of cabozantinib to FLT3-ITD cell line MV4-11 (IC50< 10nM) in vitro. After drug treatment, inhibition of active FLT3 and its downstream signaling pathway was detected as well. In xenograft model, cabozantinib effectively suppressed MV4-11 tumor growth through FLT3 inhibition and increased the survival of mice (p<0.01). To evaluate the possible application of cabozantinib in AML patients with chemotherapeutic resistance, we also tested a cell line MV4-11R established in our lab beforehand, which is resistant to cytarabine, a chemotherapeutic agent for AML. The results showed that MV4-11R was sensitive to cabozantinib in vitro. Valid inhibition of MV4-11R tumor growth and the extension of survival after treatment could be found in vivo. To evaluate the efficacy of cabozantinib, we further investigated several factors, which have been identified to confer drug resistance. Compared to normal condition, cabozantinib inhibited MV4-11 and MV4-11R cell growth with increased IC50 under either FL stimulation or stromal environment, implicating less drug sensitivity. Higher concentration of cabozantinib treatment in a short period still displayed strong inhibition on FLT3 pathway. The inhibitory effect of cabozantinib on FLT3 pathway could be influenced by human plasma environment. Moreover, we examined the sensitivity of primary bone marrow mononuclear cells to cabozantinib ex vivo. Reduction of cell viability and decreased level of phosphorylated FLT3 were both detected in FLT3-ITD AML cells. In brief, these results demonstrate cabozantinib as an effective inhibitor for FLT3-ITD AML cells growth both in vitro and in vivo, and it could be a potential target therapeutic agent for AML treatment. Further investigation on underlying drug resistance of cabozantinib is needed. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:43:50Z (GMT). No. of bitstreams: 1 ntu-104-R02424008-1.pdf: 2615682 bytes, checksum: 184c435bb0062957986c460a79cbf610 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 目錄 目錄 I 圖目錄 IV 附表目錄 V 縮寫表 VI 摘要 VII Abstract IX 第一章 前言 1 1.1 急性骨髓性白血病簡介 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-ITD(FMS-like tyrosine kinase 3-internal tandem duplication) 2 1.3 Cabozantinib介紹 3 1.4 現今TKI(tyrosine kinase inhibitor)的治療限制 4 第二章 研究目的 6 第三章 材料與方法 7 3.1. 材料 7 3.1.1. 細胞 7 3.1.2. 實驗動物 7 3.1.3. 儀器設備 7 3.1.4. 藥品 8 3.1.5. 抗體 10 3.1.6. 試劑組 11 3.1.7. 試劑藥品配置 11 3.2. 方法 14 3.2.1. 細胞培養 14 3.2.2. 細胞抑殺試驗 (MTS assay) 14 3.2.3. 細胞萃取物製備 14 3.2.4. 蛋白質定量 14 3.2.5. 西方墨點法 15 3.2.6. 基質細胞培養液收集 16 3.2.7. 正常血漿(Normal pooled plasma)製備 16 3.2.8. 單核細胞分離 16 3.2.9. 老鼠飼養 16 3.2.10. 老鼠異種移植 16 3.2.11. 腫瘤萃取物製備 17 3.2.12. 腫瘤組織包埋前處理 17 3.2.13. 免疫組織化學染色(Immunohistochemical staining) 17 3.2.14. 統計方法 18 第四章 實驗結果 19 4.1. Cabozantinib能抑殺FLT3-ITD細胞株並抑制FLT3及其下游訊息傳遞的活化 19 4.2. Cabozantinib在in vivo中對FLT3-ITD AML細胞株之腫瘤抑制情形 19 4.3. Cabozantinib抑制化療藥物AraC抗藥細胞株生長及其FLT3下游訊息傳遞之活化 21 4.4. Cabozantinib在in vivo對AraC抗藥細胞株腫瘤生長之抑制情形 21 4.5. Cabozantinib在FLT3配體刺激下對FLT3-ITD細胞株之抑制情形 22 4.6. Cabozantinib在基質細胞環境下對FLT3-ITD細胞株有抑制效果 23 4.7. Cabozantinib在人類血漿當中對FLT3-ITD細胞株訊息傳遞之影響 23 4.8. Cabozantinib對AML病人初代細胞之毒殺及抑制情形 24 第五章 討論 25 第六章 參考文獻 30 圖 38 附圖 61 附表 66 | |
dc.language.iso | zh-TW | |
dc.title | 探討選擇性抑制劑cabozantinib在in vitro及in vivo 針對帶有 FLT3-ITD突變之難治型急性骨髓性白血病的抑殺效果 | zh_TW |
dc.title | Exploration of cabozantinib as selective inhibitor against refractory acute myeloid leukemia with FLT3-ITD mutations in vitro and in vivo | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 周文堅(Wen-Chien Chou),歐大諒(Da-Liang Ou),蘇剛毅(Kang-Yi Su),顧雅真(Ya-Chen Ko) | |
dc.subject.keyword | 急性骨髓性白血病,FLT3-ITD,cabozantinib,MV4-11,抗藥性, | zh_TW |
dc.subject.keyword | Acute myeloid leukemia,FLT3-ITD,Cabozantinib,drug resistance,MV4-11, | en |
dc.relation.page | 67 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2015-08-11 | |
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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