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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張震東 | |
| dc.contributor.author | Jia-Feng Mao | en |
| dc.contributor.author | 毛嘉鳳 | zh_TW |
| dc.date.accessioned | 2021-06-17T03:42:54Z | - |
| dc.date.available | 2023-03-02 | |
| dc.date.copyright | 2018-03-02 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-02-05 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70089 | - |
| dc.description.abstract | Afatinib (BIBW 2992, Gilotrif™, Giotrif®) 為美國Boehringer Ingelheim公司所研發出來的非小細胞肺癌 (NSCLC) 標靶藥物，能以不可逆的方式共價鍵結在ErbB家族的EGFR、HER2與HER4的酪胺酸激酶上，阻斷酪胺酸激酶的磷酸化，抑制促進癌細胞生長的下游訊息傳遞。此外，Afatinib的優勢為能克服對前一代非小細胞肺癌藥物Erlotinib與Gefitinib產生的抗藥性突變 (T790M與L858R)，藉此提昇對藥物產生抗性病人的存活時間。我們實驗室先前利用自行開發的藥物目標蛋白鑑定方法 (TISTA)，發現了Afatinib不但能以EGFR作為目標蛋白，亦能以核糖核苷酸還原酶 (RNR) 作為藥物標靶，對於開拓藥物的使用範圍與合併療法提供了一些參考。在本研究中，我們由先前鑑定出可能為Afatinib的標靶蛋白中，選出與RNR具有類似功能，在核苷酸代謝中扮演重要角色的酵素，分別為DTYMK、ADSL、Nm23-H1/H2/H3、GMPS，探討其是否真的為 Afatinib的標靶蛋白。實驗結果發現DTYMK、ADSL、Nm23-H1/H2/H3、GMPS在高濃度的Afatinib 處理下，皆產生降解的現象，在低濃度時，則產生了蛋白質累積的現象，間接表示這四個蛋白皆為Afatinib的作用標靶。將處理的時間拉長到七十二小時，Afatinib在低濃度的劑量下就對四個蛋白質產生了影響。加入蛋白質降解抑制劑後，實驗結果顯示 DTYMK 與 Nm23-H1/H2/H3 是走溶酶體降解路徑，而ADSL、GMPS則現象不明顯。在低濃度時觀察到的蛋白質累積現象，實驗結果發現DTYMK、ADSL、GMPS皆是由於蛋白質生合成路徑而增加，而Nm23-H1/H2/H3則不明顯，由以上實驗結果顯示，Afatinib的確會對這四個蛋白質造成影響，很有潛力用來治療這四個蛋白質變異所造成的疾病。 | zh_TW |
| dc.description.abstract | Afatinib (BIBW 2992, Gilotrif™, Giotrif®) is a drug developed by Boehringer Ingelheim to treat non-small cell lung cancer as targeted therapy. Afatinib can act as an irreversible covalent inhibitor of the tyrosine kinases in the ErbB family (EGFR, HER2, HER4), which control cell signaling for cell survival, proliferation and metastasis. The advantage of afatinib is that it can overcome drug resistance mutation (T790M and L858R) induced by the noncovalent non-small lung cancer drugs (erlotinib and gefitinib) and extend the survival time of drug-resistant patients. Our laboratory previously has developed a drug target identification method (TISTA) and found that afatinib can not only target EGFR but also inhibit ribonucleotide reductase (RNR) as a direct target. This finding can serve as a foundation for further research on drug indications and combination therapy using afatinib. In this study, from a list of potential target proteins of afatinib, we selected four enzymes that have similar functions to RNR in nucleotide metabolism. These potential target proteins are DTYMK, ADSL, Nm23-H1/H2/H3, and GMPS. We aimed to investigate whether or not they are truly target proteins for afatinib. The results showed that the degradation of thymidylate kinase (DTYMK), adenylosuccinate lyase (ADSL), nucleoside diphosphate kinase (Nm23-H1/H2/H3) and GMP synthase (GMPS) in cells occurred when the cells were treated with 10 μM afatinib. However, when the cells were treated with lower concentrations of afatinib, these proteins accumulated, due to increased protein synthesis (DTYMK, ADSL and GMPS) or decreased protein degradation (Nm23-H1/H2/H3). Using various protein degradation inhibitors, it was found that DTYMK and Nm23-H1/H2/H3 degradation was mediated by lysosomal pathways. In conclusion, afatinib does affect these four proteins and has great potential for treating diseases caused by changes in these four proteins. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T03:42:54Z (GMT). No. of bitstreams: 1 ntu-107-R02b46020-1.pdf: 12084733 bytes, checksum: b55eed0d3132887adcea18f7b2d546f6 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 目錄
致謝 i 中文摘要 ii 英文摘要 iii 縮寫表 v 目錄 viii 第一章 緒論 1 1.1 非小細胞肺癌 (Non-small cell lung cancer, NSCLC) 1 1.2 表皮生長因子 (EGF) 與表皮生長因子受體 (EGFR) 2 1.3 Afatinib 4 1.4 小分子藥物的目標鑑定 5 1.4.1 小分子藥物的發展 5 1.4.2 藥物目標鑑定方法 6 1.5 共價藥物 8 1.6 麥可加成反應 (Michael Addition) 11 1.7 Afatinib作用之其他標靶蛋白 12 1.7.1 DTYMK (deoxythymidylate kinase) 12 1.7.2 Nm23-H1/H2/H3 13 1.7.3 ADSL (Adenylosuccinate lyase) 14 1.7.4 GMPS (guanine monophosphate synthetase) 16 1.8 研究動機 17 第二章 材料與實驗方法 18 2.1 細胞實驗方法 18 2.1.1 細胞培養 (cell culture) 18 2.1.2 細胞繼代 18 2.1.3 藥物處理細胞 18 2.2 蛋白質實驗方法 19 2.2.1 細胞蛋白質樣本製備 19 2.2.2 十二烷基硫酸鈉聚丙烯醯胺凝膠電泳 (Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis, SDS-PAFE) 19 2.2.3 蛋白質轉印 21 2.2.4 西方點墨法 (Western Blot) 21 第三章 結果 23 3.1 處理Afatinib二十四小時對於Nm23-H1/H2/H3、DTYMK、GMPS、ADSL蛋白質表現量的影響 23 3.2 處理Afatinib四十八小時對於Nm23-H1/H2/H3、DTYMK、GMPS、ADSL蛋白質表現量的影響 24 3.3 處理Afatinib七十二小時對於Nm23-H1/H2/H3、DTYMK、GMPS、ADSL蛋白質表現量的影響 26 3.4 Afatinib使DTYMK降解是經由Lysosome degradation pathway 27 3.5 Afatinib使Nm23-H1/H2/H3降解是經由Lysosome degradation pathway 28 3.6 Afatinib誘導GMPS與ADSL降解路徑的探討 28 3.7 Afatinib是經由蛋白質生合成途徑促使的DTYMK蛋白質表現量上升 29 3.8 Afatinib是經由蛋白質生合成途徑促使GMPS蛋白質表現量上升 30 3.9 Afatinib是經由蛋白質生合成途徑促使ADSL蛋白質表現量上升 31 3.10 Afatinib影響Nm23-H1/H2/H3蛋白質表現量之探討 31 第四章 討論 33 4.1 標靶藥物的專一性 33 4.2 以抗體尋找藥物目標蛋白 34 4.3 藥物標靶蛋白鑑定於合併療法的應用 35 4.4 Afatinib造成細胞內Nm23-H1/H2/H3、DTYMK、GMPS、ADSL降解路徑之探討 36 4.5 Afatinib誘導Nm23-H1/H2/H3、DTYMK、GMPS、ADSL蛋白質表現量上升之探討 37 第五章 結語 38 第六章 實驗結果圖表 39 圖1 處理24小時Afatinib濃度遞增對於ADSL、Nm23-H1/H2/H3、GMPS、DTYMK蛋白質表現量影響 39 圖2 處理48小時Afatinib濃度遞增對於ADSL、Nm23-H1/H2/H3、GMPS、DTYMK蛋白質表現量影響 40 圖3 處理72小時Afatinib濃度遞增對於ADSL、Nm23-H1/H2/H3、GMPS、DTYMK蛋白質表現量影響 41 圖4 Afatinib促使ADSL、Nm23-H1/H2/H3、GMPS、DTYMK降解的路徑 42 圖5 合併處理 Afatinib 與 Cycloheximide 探討蛋白質累積現象原因 43 第七章 參考文獻 44 第八章 附錄 50 附圖1 表皮生長因子二聚化過程與訊息傳遞路徑 50 附圖2 EGFR的突變位置 51 附圖3 Afatinib的化學結構和可被親核基攻擊的位置 52 附圖4 以ABPP (activity-based protein profiling) 鑑定藥物目標蛋白流程 53 附圖5 小分子目標蛋白鑑定方法：正向選擇與負向選擇 54 附圖6 麥可加成反應 (Michael Addition) 55 附圖7 PC14處理不同濃度與時間Afatinib的訊號模式 56 附圖8 合併 Afatinib 與 Doxorubicin 處理PC14細胞 57 | |
| dc.language.iso | zh-TW | |
| dc.subject | 阿法替尼 | zh_TW |
| dc.subject | 共價藥物 | zh_TW |
| dc.subject | 麥可加成反應 | zh_TW |
| dc.subject | afatinib | en |
| dc.subject | Michael addition | en |
| dc.subject | covalent drug | en |
| dc.title | 抗癌藥物afatinib作用EGFR外之其它標靶蛋白 | zh_TW |
| dc.title | Effects of afatinib through other target proteins than EGFR | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳宏文,張?仁,張茂山 | |
| dc.subject.keyword | 共價藥物,麥可加成反應,阿法替尼, | zh_TW |
| dc.subject.keyword | afatinib,covalent drug,Michael addition, | en |
| dc.relation.page | 57 | |
| dc.identifier.doi | 10.6342/NTU201800334 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-02-06 | |
| 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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