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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李財坤(Tsai-Kun Li) | |
| dc.contributor.author | Chieh-Hua Lee | en |
| dc.contributor.author | 李玠樺 | zh_TW |
| dc.date.accessioned | 2021-06-16T16:08:20Z | - |
| dc.date.available | 2018-09-24 | |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-05-23 | |
| dc.identifier.citation | Andoh, T., and Ishida, R. (1998). Catalytic inhibitors of DNA topoisomerase II. Biochim Biophys Acta 1400, 155-171.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62717 | - |
| dc.description.abstract | 抗癌藥物蒽醌(anthracenediones)，如：雙羥蒽醌(mitoxantrone)及阿美蒽醌(ametantrone)，其抗癌的活性目前認為是利用藥物嵌入DNA雙股螺旋中，增加DNA斷裂接合點的距離，造成斷點接合(religation)的困難度 (稱為錯位機制，misalignment mechanism)，進而引起第二型DNA 拓樸異構酶(TOP2)所主導的DNA損傷，殺害癌細胞。然而，此類藥物因結構上造成的多重抗藥性以及DNA 嵌入能力相關的細胞毒性卻嚴重限制了它們在臨床治療上的效果。為了改善此類藥物的作用，本論文藉由探討一系列雙羥蒽醌及阿美蒽醌-胺基酸衍生物(M/AACs)的作用機制，以期發現更有效且副作用較低的化合物。我們的實驗首先發現此類衍生物的確能有效地造成癌細胞死亡，而且此種現象與藥物引發的DNA 損傷有良好的正相關性。同時衍生物中的先導化合物(lead compound)1,4-bis-L/L-methionine-conjugated MAC (L/LMet-MAC)不管在細胞毒性還是造成DNA 損傷的能力都可以媲美甚至超越臨床用藥-雙羥蒽醌。而在藥物與DNA 的作用方面，無論L 構型還是D 構型的藥物解開DNA 螺旋的能力都比雙羥蒽醌及阿美蒽醌弱許多。同時我們亦提供許多證據顯示TOP2 在L/LMet-MAC 所造成的DNA斷裂和細胞毒性中扮演決定性的角色；例如：像是相對於TOP2 表現正常的HL-60細胞，在TOP2 缺失的HL-60/MX2 細胞中可看到由L/LMet-MAC 引起的DNA 斷裂及細胞死亡的現象明顯下降；另外，RNA 干擾 (RNAi) 實驗結果顯示兩種人類TOP2 異構酶，hTOP2α和 hTOP2β，在L/LMet-MAC 引起的DNA 損傷及細胞死亡中可能分別扮演不同的角色。再者，L/LMet-MAC 引起的DNA 斷裂是可逆的，並且能被TOP2 的抑制劑(例：ICRF-193…等)中和抵消。我們還在胞外(in vitro)的生化實驗證明L/LMet-MAC 直接作用於TOP2 產生DNA 斷裂，以及在細胞內引起TOP2 可切性複合體(TOP2 cleavable complex, TOP2cc)形成的證據。有趣的是，D構型的化合物不管在造成的DNA 斷裂和細胞毒性的能力都比相對L 構型的化合物來得差。綜合以上的實驗結果顯示此類M/AAC 藥物作用於TOP2 的方式是與化合物本身結構有關，似乎暗示了另一種藥物與酵素和DAN 交互作用的新機制。另外實驗結果亦指出，L/LMet-MAC 並不像雙羥蒽醌是多重抗藥性運載體(multi-drug resistance transporter，像是MDR1)的受質。綜合來說，我們發現了L/LMet-MAC 這類化合物，能改善臨床用藥蒽醌的藥物臨床副作用並加強了其抗癌的效果，為將來TOP2 相關抗癌藥物的開發開啟了新的一頁。 | zh_TW |
| dc.description.abstract | Antitumor anthracenediones, including mitoxantrone (MX) and ametantrone (AT), intercalate into DNA duplexes and induce topoisomerase II (TOP2)-mediated DNA break via a proposed “misalignment” mechanism. However, structure-associated multi-drug resistance and DNA unwinding ability have greatly limited their clinical usage. Here, a series of 1,4-bis(2-amino-ethylamino) MX- and AT-amino acid conjugates (M/AACs) were characterized. We showed that abilities in cancer cell killing correlate with the amounts of chromosomal DNA breaks induced by M/AACs. Notably, the 1,4-bis-L/L-methionine-conjugated MAC (L/LMet-MAC) exhibits cancer cell-killing, DNA breaking and anti-tumor activities rivaling those of MX. However,the L- and D-form Met-M/AACs unwind DNA weakly compared to MX and AT. Moreover, the roles of the two human TOP2 isozymes (hTOP2α and 2β) in L/LMet-MAC-induced DNA breakage and cytotoxicity were suggested by the following observations: (i) M/AAC-induced DNA breakage, cytotoxicity and apoptosis are greatly reduced in TOP2-deficient conditions; (ii) DNA breaks induced by MACs are highly reversible and effectively antagonized by TOP2 catalytic inhibitors; (iii) MACs directly induced hTOP2-mediated DNA cleavage in vitro and formation of hTOP2 / cc in the cell culture system. Interestingly, D-aa-conjugated MACs often caused a lower level in hTOP2-mediated DNA breaks and cancer cell-killing than the corresponding L-form ones suggesting a novel steric-specific TOP2-targeting mechanism of MACs. These results are consistent with a mechanistic model where both enzyme- and DNA-drug interactions contribute to novel TOP2-targeting by M/AACs. Furthermore, unlike MX and AT, Met-MACs are poor substrates for the multi-drug resistant pumps. Since MX and M/AACs all exhibit fluorescent properties, the drug efflux mediated by multi-drug resistant pumps are also studied. The results are also consistent with the cytotoxicity study that Met conjugate(s) convert MX and AT into poor substrates for MDR1 and BCRP transporters. Therefore, L/LMet-MAC represents a promising class of TOP2-targeting drugs with reduced side-effects and unwanted toxicity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T16:08:20Z (GMT). No. of bitstreams: 1 ntu-102-F95445103-1.pdf: 2814870 bytes, checksum: 192af2d2f544e7cc3dca4aa9800736ac (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 中文摘要……………………………………………………………………………...I
ABSTRACT…………………………………………………………………………III ABBREVIATION……………………………………………………………………V INTRODUCTION…………………………………………………………………....1 1. DNA topoisomerase 1.1. Type I and Type II DNA topoisomerase 1.2. Topoisomerase II (TOP2) and their catalytic cycle 2. TOP2-targeting and poisoning 2.1. TOP2-targeting anticancer drugs 2.2. Crrent issue of TOP2-based anticancer drugs 3. Anthracenedione-methionine conjugates 3.1. Mitoxantrone 3.2. Mitoxantrone-amino acid conjugates (MACs) SPECIFIC AIMS……………………………………………………………………10 MATERIALS & METHODS……………………………………………………….12 - Chemicals, plasmids and cell lines - Antibodies and immunoblotting analysis - Cytotoxicity assay (MTT assay) - Alkaline single cell gel electroforesis assay (Comet assay) - Apoptotic DNA laddering - Lentivirus-based RNA interference (RNAi) - In vitro cleavage assay - Isolating in vivo complexes of enzyme to DNA (ICE bioassay) - DNA-unwinding assays - Antitumor activity against SCID mice carrying human tumor xenografts - DNA binding Assay - FACScan flow cytometric analysis RESULTS……………………………………………………………………………20 - Extents of DNA breakage induced by Mitoxantrone (MX)- and ametantrone (AT)-amino acid conjugates (M/AACs) positively correlates with their abilities in cancer cell killing - The steric-specific effect of the L/D-form amino acid (aa) conjugates in cell killing and DNA breakage induced by M/AACs - Like other TOP2-targeting drugs, L/LMet-MAC also activates different DNA damage responces - Both cancer cell killing and DNA breakage induced by M/AACs are reduced in TOP2-deficient HL-60/MX2 cells - hTOP2α plays a more critical role in the L/LMet-MAC-induced DNA damage and cancer cell killing than hTOP2β - L/LMet-MAC traps hTOP2 cleavable complexes (hTOP2cc) better than MX - L/LMet-MAC is a more efficacious anti-cancer agent than MX in mouse models - Met-MACs induce reversible hTOP2αcc in vitro, but unwinds DNA poorly - L/LMet-MAC cytotoxicity is not significantly affected by the activity of MDR1 DISCUSSION………………………………………………………………………29 - L/LMet-M/AAC induces TOP2-mediated DNA damage and cytotoxicity - L/LMet-M/AAC has improved therapeutic avtivity - Reduced susceptibility of L/LMet-M/AAC to resisitence mediated by membrane transporter - A novel TOP2-targeting mechanism of L/LMet-M/AAC REFERENCES……………………………………………………………………....34 CURRICULUM VITAE……………………………………………………………..44 FIGURES & TABLES……………………………………………………………….49 | |
| dc.language.iso | en | |
| dc.subject | 多重抗藥性 | zh_TW |
| dc.subject | 雙羥??胺基酸衍生物 | zh_TW |
| dc.subject | 雙羥?? | zh_TW |
| dc.subject | 第二型DNA拓樸異構?致癌細胞毒性 | zh_TW |
| dc.subject | topoisomerase II | en |
| dc.subject | cancer cell-killing | en |
| dc.subject | mitoxantrone | en |
| dc.subject | mitoxantrone- and ametantrone-amino acid conjugates | en |
| dc.subject | multi-drug resistance | en |
| dc.title | 探討蒽醌-胺基酸衍生物做為以第二型拓樸異構酶為標的之抗癌藥物的機制與臨床優勢 | zh_TW |
| dc.title | Anthracenedione-methionine conjugates as a novel class of topoisomerase II-targeting anticancer drugs with favorable clinical profiles | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 顧記華(Jih-Hwa Guh),鄧述諄(Ｓhu-Chun Teng),詹迺立(Nei-Li Chan),李明學(Ming-Shyue Lee) | |
| dc.subject.keyword | 第二型DNA拓樸異構?致癌細胞毒性,雙羥??,雙羥??胺基酸衍生物,多重抗藥性, | zh_TW |
| dc.subject.keyword | topoisomerase II,cancer cell-killing,mitoxantrone,mitoxantrone- and ametantrone-amino acid conjugates,multi-drug resistance, | en |
| dc.relation.page | 98 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-05-23 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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