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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張震東(Geen-Dong Chang) | |
dc.contributor.author | Yueh-Ting Pan | en |
dc.contributor.author | 潘岳廷 | zh_TW |
dc.date.accessioned | 2021-06-17T02:31:19Z | - |
dc.date.available | 2027-07-27 | |
dc.date.copyright | 2017-08-25 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-17 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68702 | - |
dc.description.abstract | AZD-9291(Osimertinib, TagrissoTM)是由美國AstraZeneca所開發的非小型細胞肺癌的口服標靶藥物,其作用機制主要為抑制表皮生長因子受體(epidermal growth factor receptor tyrosine kinase, EGFR)的活化來抑制癌細胞的生長,為第三代EGFR的抑制劑。AZD-9291主要是針對EGFR發生T790M時的結構變異所設計,此變異也是非小型細胞肺癌患者對前兩代藥物產生抗性的主因。
核糖核苷酸還原酶的功能為轉換核糖核苷酸成去氧核糖核苷酸,提供DNA的合成與修補的先驅物。由於癌細胞的去氧核醣核苷酸來源主要依靠de novo pathway中核糖核苷酸還原酶來產生,目前研究發現與正常的細胞相比癌細胞會提升其核糖核苷酸還原酶的活性或表現量。我們實驗室先前藉新開發的方法學,發現核糖核苷酸還原酶為第二代EGFR抑制劑Afatinib的目標之一,在這篇論文中,我們發現AZD-9291對於核糖核苷酸還原酶與Afatinib有相同的抑制作用,而其效果更佳。長時間對H1975細胞處理AZD-9291後,我們發現構成核糖核苷酸還原酶的兩個次單位M1及M2都有顯著的下降,經過72小時藥物的處理,只需要1 nM的藥物濃度即可看見效果。目前治療胰臟癌的用藥主要為Gemcitabine,Gemcitabine藉由阻止DNA鏈的延長與抑制核醣核苷酸的活性來殺死癌細胞,然而研究發現胰臟癌細胞往往藉由提高核糖核苷酸還原酶的表現量來產生抗性,根據我們的研究結果,我們發現AZD-9291不只可以用來治療非小型細胞肺癌,對胰臟癌細胞也有一定的效果。 我們也利用實驗室開發的新方法學Target identification by specific tagging and antibody detection (TISTA),以抗AZD-9291的血清做為媒介來找尋其他AZD-9291可能作用的目標。此抗血清的用途很廣泛,包含免疫墨點法、免疫螢光染色和免疫沉澱都可以使用。藉由使用抗AZD-9291血清行免疫沉澱,再經由質譜儀的分析,我們將可發現AZD-9291更多潛在的作用目標。也因為如此,這個新方法學可以用來找尋共價藥物潛在的目標。 | zh_TW |
dc.description.abstract | AZD-9291(Osimertinib, TagrissoTM) is an oral, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that has been developed by AstraZeneca for the treatment of advanced non-small cell lung cancer (NSCLC). AZD-9291 has been designed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. According to the previous studies from our lab, ribonucleotide reductase (RNR) is a novel target of Afatinib, a second-generation EGFR TKI of NSCLC. RNR is the enzyme responsible for the conversion of ribonucleotides to 2’-deoxyribonucleotides and thereby provides the precursors needed for both synthesis and repair of DNA. Nowadays, researches have indicated that cancer cells may enhance their RNR expression due to their dependence of RNR for de novo dNTP biosynthesis. Here, we found that AZD-9291 has the same action as Afatinib on RNR and its effect is more potent. Long-term AZD-9291 treatment in H1975 cell causes significant decrease in the protein levels of RNR and both M1 and M2 subunit protein levels decline in cells treated with 1 nM AZD-9291 for 72 hours. Gemcitabine has been used to treat pancreatic cancer, however, pancreatic cancer cells acquire resistance through elevating the expression of RNR. Our data suggest that AZD-9291 may not only provide therapeutics advantage in lung cancer but also in pancreatic cancer.
We have also used target identification by specific tagging and antibody detection (TISTA), to unravel other potential targets of AZD-9291 using an antiserum against AZD-9291. The antiserum can be used in general antibody-based assays such as immunoblotting, immunofluorescence staining and immunoprecipitation. Target identification through immunoprecipitation and Mass spectrometric analysis reveals potential targets of AZD-9291. Therefore, this novel approach can be used in the identification of potential targets of covalent drugs. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T02:31:19Z (GMT). No. of bitstreams: 1 ntu-106-R04b46015-1.pdf: 4012349 bytes, checksum: 46df57d5a47028ee9f973f972ed9a1e7 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 口試委員會審定書............................................................................................................ i
謝誌................................................................................................................................... ii 中文摘要.......................................................................................................................... iii 英文摘要.......................................................................................................................... iv 縮寫表.............................................................................................................................. vi 目錄.................................................................................................................................. ix 圖目錄............................................................................................................................ xiii 第一章 緒論..................................................................................................................... 1 第一節 非小型細胞肺癌......................................................................................... 1 第二節 表皮生長因子受體..................................................................................... 2 第一項 表皮生長因子..................................................................................... 2 第二項 表皮生長因子受體與其訊息傳遞路徑............................................. 3 第三項 表皮生長因子受體的運送................................................................. 4 第四項 表皮生長因子受體的突變與非小型細胞肺癌................................. 5 第三節 表皮生長因子受體酪氨酸激酶抑制劑..................................................... 6 第一項 蛋白質的磷酸化與激酶..................................................................... 6 第二項 第一代表皮生長因子受體酪氨酸激酶抑制劑................................. 7 第三項 第二代表皮生長因子受體酪氨酸激酶抑制劑................................. 7 第四項 第三代表皮生長因子受體酪氨酸激酶抑制劑................................. 8 第五項 第四代表皮生長因子受體酪氨酸激酶抑制劑................................. 9 第四節 AZD-9291................................................................................................. 10 第五節 核糖核苷酸還原酶................................................................................... 11 第一項 去氧核糖核苷三磷酸的合成........................................................... 11 第二項 異位調控與反應機制....................................................................... 13 第三項 Gemcitabine...................................................................................... 14 第六節 麥可加成反應........................................................................................... 16 第七節 小分子藥物的目標鑑定........................................................................... 16 第一項 小分子藥物的發展........................................................................... 16 第二項 藥物目標鑑定方法........................................................................... 17 第三項 TISTA................................................................................................ 19 第八節 研究動機................................................................................................... 20 第二章 實驗材料與方法............................................................................................... 21 第一節 實驗材料................................................................................................... 21 第二節 細胞學實驗方法....................................................................................... 21 第一項 細胞培養........................................................................................... 21 第二項 冷凍/解凍細胞................................................................................. 22 第三項 細胞繼代........................................................................................... 22 第四項 抑制藥物之處理............................................................................... 22 第五項 細胞核與細胞質分離....................................................................... 22 第六項 細胞質、粒線體與細胞核分離....................................................... 23 第七項 細胞存活率分析............................................................................... 24 第三節 蛋白質實驗方法....................................................................................... 24 第一項 細胞蛋白質樣本製備....................................................................... 24 第二項 BCA蛋白質定量............................................................................. 25 第三項 十二烷基硫酸鈉聚丙烯醯胺凝膠電泳........................................... 25 第四項 電泳轉移........................................................................................... 26 第五項 西方墨點法....................................................................................... 26 第六項 免疫沉澱........................................................................................... 27 第七項 細胞外核糖核苷酸還原酶的修飾和競爭實驗............................... 28 第四節 反轉錄....................................................................................................... 29 第五節 即時聚合酶鏈式反應............................................................................... 29 第六節 抗體製備................................................................................................... 30 第一項 小分子藥物抗原製備....................................................................... 30 第二項 胜肽 (Peptide) 抗原製備.............................................................. 31 第三項 抗AZD-9291之多株抗體純化....................................................... 31 第四項 抗目標蛋白之多株抗體純化........................................................... 31 第三章 結果................................................................................................................... 33 第一節 AZD-9291可以抑制不同種癌細胞的生長.......................................... 33 第二節 AZD-9291 可以造成細胞內核糖核苷酸還原酶的下降..................... 33 第三節 AZD-9291 造成核糖核苷酸還原酶小次單元的下降不需要進細胞核 34 第四節 核糖核苷酸還原酶為AZD-9291的直接目標之一............................. 35 第五節 AZD-9291和Gemcitabine對ASPC-1細胞存活率影響的比較........ 36 第六節 短時間對ASPC-1處理Gemcitabine造成核糖核苷酸還原酶降解... 36 第七節 長時間對ASPC-1細胞處理Gemcitabine造成核糖核苷酸還原酶RRM2B表現量上升 37 第八節 AZD-9291可以促使誘導增加的RRM2B降解.................................. 39 第九節 對癌細胞同時處理AZD-9291與Gemcitabine效果更好................... 39 第十節 抗AZD-9291血清的應用..................................................................... 40 第四章 討論................................................................................................................... 42 第一節 標靶藥物的專一性................................................................................. 42 第二節 AZD-9291能造成癌細胞內核糖核苷酸還原酶降解.......................... 43 第三節 AZD-9291與Gemcitabine的合併療法................................................ 45 第四節 以抗體搜尋AZD-9291的目標蛋白..................................................... 46 第五章 結語................................................................................................................... 48 第六章 實驗結果圖表................................................................................................... 49 參考文獻......................................................................................................................... 66 附錄................................................................................................................................. 77 | |
dc.language.iso | zh-TW | |
dc.title | 利用抗體辨認發現AZD-9291能造成核糖核苷酸還原酶的降解來抑制癌細胞生長 | zh_TW |
dc.title | Antibody-based target identification reveals AZD-9291 repressing cancer cells via down-regulation of ribonucleotide reductase | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張茂山(Mau-Sun Chang),陳宏文(Hungwen Chen),張?仁(Ching-Jin Chang) | |
dc.subject.keyword | AZD-9291,Gemcitabine,核糖核?酸還原?,共價藥物,TISTA, | zh_TW |
dc.subject.keyword | AZD-9291,Gemcitabine,Ribonucleotide reductase,Covalent drugs,target identification, | en |
dc.relation.page | 96 | |
dc.identifier.doi | 10.6342/NTU201703766 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-08-18 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
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