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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 冀宏源(Hung-Yuan Chi) | |
| dc.contributor.author | Min-Yu Ko | en |
| dc.contributor.author | 柯旻佑 | zh_TW |
| dc.date.accessioned | 2021-06-17T06:32:07Z | - |
| dc.date.available | 2028-12-31 | |
| dc.date.copyright | 2018-08-18 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-16 | |
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Xodo, G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acids Res, 2006. 34(9): p. 2536-49. 51. Yang, D. and L.H. Hurley, Structure of the biologically relevant G-quadruplex in the c-MYC promoter. Nucleosides Nucleotides Nucleic Acids, 2006. 25(8): p. 951-68. 52. Henderson, A., et al., Detection of G-quadruplex DNA in mammalian cells. Nucleic Acids Res, 2014. 42(2): p. 860-9. 53. Lam, E.Y., et al., G-quadruplex structures are stable and detectable in human genomic DNA. Nat Commun, 2013. 4: p. 1796. 54. Chen, B.J., et al., Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics. Int J Biol Sci, 2014. 10(10): p. 1084-96. 55. Zimmer, J., et al., Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds. Mol Cell, 2016. 61(3): p. 449-460. 56. Xu, H., et al., CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun, 2017. 8: p. 14432. 57. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72264 | - |
| dc.description.abstract | 去氧核醣核酸 (DNA) 之間的鏈間交聯 (interstrand cross-link, ICL) 是一種極具細胞毒性的DNA損傷。當雙股DNA被相互嵌合無法解開時，容易影響後續DNA複製、轉錄等重要細胞生理現象，最終導致DNA的雙股斷裂 (double-strand break, DSB)。氮芥類化合物 (nitrogen mustard) 藉由與DNA烷化反應造成鏈間交聯，如今被廣泛運用在癌症的化療藥物上。在此研究中我分析由陳昭岑教授實驗室所合成的新興烷化試劑COOH-SW相關細胞實驗，並且發現當同源修復 (homology-directed repair, HDR) 的相關重要基因如BRCA1與BRCA2缺陷時，細胞會對於COOH-SW更加敏感。
除此之外，陳昭岑教授實驗室更進一步合成COOH-SW的衍生物：BMVC-SW，其含有兩個攻擊端 (warhead)，一個是承接COOH-SW的烷化攻擊端，另一個則是一種鳥嘌呤四聯體 (G-quadruplex, G4) 的配體 (ligand) BMVC (3,6-bis (1-methyl-4-vinylpyridinium iodide) carbazole)。在BMVC-SW的相關細胞實驗分析中，利用螢光顯微鏡觀察到BMVC-SW可以穩定地嵌合在細胞核內的DNA上。在許多種癌症細胞毒性測試中，發現BMVC-SW相較於COOH-SW、BMVC以及兩者共同混合皆具有更高的細胞毒性。最重要的是BMVC-SW也和COOH-SW相似，當細胞同源修復缺陷時會對於BMVC-SW更為敏感。整體來說，在與陳昭岑教授實驗室的合作研究中，我們發現BMVC-SW比個別烷化攻擊端更具有細胞毒性，而且可以針對性地毒殺BRCA基因缺陷 (BRCA-deficient, BRCAness) 相關癌症細胞，並期望有未來更深廣的臨床相關應用。 | zh_TW |
| dc.description.abstract | DNA interstrand cross-link (ICL) is one of the most cytotoxic lesions among many kinds of DNA damages. ICLs block essential cellular processes such as DNA replication and transcription, and thus generate DNA double-strand breaks (DSBs). It has been well documented that nitrogen mustards induce ICLs by DNA alkylation on both strands. Here we introduced a new DNA alkylating agent COOH-SW, generated by Professor Chao-Tsen Chen’s lab. Interestingly, my cell-based studies showed that cancer cells defective in a homology-directed repair (HDR), such as BRCA1/2-deficient cells, are sensitive to COOH-SW.
Furthermore, Professor Chen’s lab further synthesized a novel DNA alkylator that combines alkylating warhead of COOH-SW and G-quadruplex (G4) ligand 3,6-bis (1-methyl-4-vinylpyridinium iodide) carbazole (BMVC) named BMVC-SW. Cell-based fluorescent images evidenced that BMVC-SW steadily bound to nucleus DNA. Moreover, I found BMVC-SW had more cytotoxicity than COOH-SW, BMVC, and combination treatment of both together in different types of cancers. Importantly, similar to COOH-SW, my cell-based studies showed that cancer cells defective in a homology-directed repair are sensitive to BMVC-SW. Thus, our collaborative research demonstrated BMVC-SW possesses more cytotoxicity than DNA alkylator alone and reveals novel selective chemicals toward BRCA-deficient (BRCAness) cancers. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T06:32:07Z (GMT). No. of bitstreams: 1 ntu-107-R05b46003-1.pdf: 2189025 bytes, checksum: db9fd6e5381569eb37dc6c4e2f989f4a (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 誌謝 1
中文摘要 2 Abstract 4 Chapter 1 Introduction 9 1-1 DNA interstrand crosslinks (ICLs) 9 1-2 Crosslinking agents and chemotherapies 9 1-2-1 A novel alkylating agent COOH-SW 10 1-3 DNA repair of ICLs 10 1-4 G-quadruplex (G4) 11 1-5 G4 ligands and therapeutic application 12 1-6 Design of the G4-directing alkylating agent BMVC-SW 12 1-7 Motivation of my thesis study 13 Chapter 2 Materials and Methods 14 2-1 Chemicals 14 2-2 Cell lines and culture conditions 14 2-3 Immunoblotting 15 2-4 Fluorescence microscopy 17 2-5 Short-term cell viability assay 17 2-6 Long-term clonogenic survival assay 18 Chapter 3 Results 19 3-1 DNA alkylator COOH-SW specifically kills BRCA- deficient human cancer cells 19 3-2 G4-directing DNA alkylator, BMVC-SW, steadily targets on cell nucleus 20 3-3 BMVC-SW shows a higher cytotoxicity than COOH-SW and G4 ligand BMVC 20 3-4 BMVC-SW exhibits a higher cytotoxicity than COOH-SW and G4 ligand BMVC added together 21 3-5 BMVC-SW specifically kills BRCA- deficient cancer cells 22 Chapter 4 Conclusion and Discussion 23 4-1 Summary of key findings 23 4-2 Discussion 23 4-2-1 Further examine the specific targeting of BMVC-SW toward G4-DNAs 23 4-2-2 Implication of COOH-SW and BMVC-SW for cancer therapy 24 Figures 26 References 38 | |
| dc.language.iso | en | |
| dc.title | 利用DNA烷化試劑以及其衍生物標的BRCA基因缺陷癌細胞 | zh_TW |
| dc.title | Targeting BRCAness Cancer Cells with DNA Alkylator and Its Derivatives | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳昭岑(Chao-Tsen Chen),侯明宏(Ming-Hon Hou) | |
| dc.subject.keyword | 去氧核醣核酸鏈間交聯,DNA烷化試劑,鳥嘌呤四聯體,BRCA基因,標靶治療, | zh_TW |
| dc.subject.keyword | DNA interstrand crosslink,DNA alkylator,G-quadruplex,BRCA,Target therapy, | en |
| dc.relation.page | 42 | |
| dc.identifier.doi | 10.6342/NTU201803557 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-16 | |
| 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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