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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑萍 | |
| dc.contributor.author | Cheng-Po Huang | en |
| dc.contributor.author | 黃政博 | zh_TW |
| dc.date.accessioned | 2021-06-12T18:03:22Z | - |
| dc.date.available | 2011-02-19 | |
| dc.date.copyright | 2008-02-19 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-01-22 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27390 | - |
| dc.description.abstract | 由天然漆中分離出三個具有毒殺癌細胞功效的化合物，其結構為對苯二酚[1, 4 hydroquinone (HQ)]衍生物，於苯環的第二個碳的位置有17個碳的不飽和碳鏈，而此三化合物中具有最強的細胞毒性的一個，根據其化學結構命名為10′(Z),13′(E),15′(E)- heptadecatrienylhydroquinone簡稱為HQ17(3)。HQ17(3)具有毒殺多種癌細胞株的效果，因此在本篇論文中將進一步探討HQ17(3)之作用機制及成為抗癌藥物的可行性。本篇研究中發現HQ17(3)為Topoisomerase II (Topo II) poison之藥物，其作用為不可逆反應，並會造成DNA-Topo II complex的增加。本篇論文中並以細胞實驗証明HQ17(3)在細胞內的作用: HQ17(3)對於HL-60血癌細胞株的ED50為0.9 μM，然而對於Topo II有缺陷的HL-60/MX2細胞則為9.6 μM，而對於不具增生能力的人類周邊血單核球細胞則不具有毒性，由此可知HQ17(3)可以抑制細胞內Topo II的活性。此外，HQ可以透過產生氧化壓力的方式引發細胞死亡，而這能透過給予N-acetylcysteine (NAC)降低細胞內氧化壓力，將傷害降低而保護細胞，但此保護措施在HQ17(3)引起的細胞死亡現象上並不顯著。由此可知，HQ17(3)雖然具有與HQ相似的結構，但是HQ17(3)卻具有較強的細胞毒殺效果，而且和HQ引起細胞死亡的方式不相同。本論文中並以肝癌細胞株Huh7進行研究，發現HQ17(3)能在短時間內進入Huh7細胞內抑制DNA合成，而此抑制DNA合成應來自於Topo II活性受到抑制，造成DNA的傷害進而啟動DNA damage相關的基因反應，實驗中偵測到caspase-9及-3的活化及凋亡相關基因的活化，因此不同癌細胞中對於HQ17(3)的反應不同。研究中也以動物實驗研究HQ17(3)成為抗癌藥物的可行性，包括將Huh7以三度空間生長的方式培養並移植到小鼠皮下，給予HQ17(3)可引發Huh7的凋亡；以肺癌細胞株Lewis lung carcinoma接種於小鼠皮下再給予HQ17(3)治療，結果顯示能有效抑制腫瘤生長及轉移，而藥物毒性的測試部分，以HQ17(3)注射於F344大鼠的皮下，於28天後分析大鼠的血液生化值，由結果顯示HQ17(3)並不會引發臨床上的毒性反應，因此HQ17(3)具有發展成為抗癌藥物的潛力，而其特殊的結構可作為將來設計抗癌藥物的參考。 | zh_TW |
| dc.description.abstract | Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family. Each of them has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10′(Z),13′(E),15’(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. In this study, we have shown that HQ17(3) was a topoisomerase (Topo) II poison and the inhibition was irreversible through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC50 of 0.9 μM, inhibited theTopo-II deficient cells HL-60/MX2 with an EC50 of 9.6 μM, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 μM. Therefore, the inhibition of Topo II plays an important role in HQ17(3) induced cell death. Since HQ17(3) was structurally similar to HQ, the comparison of the effects induced by HQ and HQ17(3) was demonstrated.HQ17(3) presents the same ability to trigger oxidative damage as HQ. However, when given an anti-oxidant agent, N-acetylcysteine, the cytotoxic effect of HQ can be significantly diminished but not HQ17(3). Therefore, HQ17(3) exhibit an ability to induce cell death in cancer cell through different pathway from HQ. In another part of this study, HQ17(3) was found to induce apoptosis in hepatoma cell line, Huh7. After HQ17(3) treatment, over expression of several DNA damage-related and apoptosis-related genes can be detected by cDNA microarray. Besides, the activation of caspase pathway was also detected. In animal experiments, HQ17(3) can inhibit the growth and metastasis of Lewis lung carcinoma cells induced tumor. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-12T18:03:22Z (GMT). No. of bitstreams: 1 ntu-97-D92424003-1.pdf: 6545173 bytes, checksum: 9d0b9258475720b332a044d76e6ee6b2 (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | 中文摘要------------------------------------------------------------------------------------------7
英文摘要------------------------------------------------------------------------------------------8 縮寫表-------------------------------------------------------------------------------------------10 一. 序論-----------------------------------------------------------------------------------------11 1.1 漆樹及漆酚 (urushiol)的成份-----------------------------------------------------11 1.2 對苯二酚 (HQ)之相關研------------------------------------------------------------12 1.3 拓樸異構酶 II (Topoisomerase II)-----------------------------------------------13 1.4 細胞凋亡--------------------------------------------------------------------------------16 1.5 三度空間細胞培養 (3-dimension culture)系統 -------------------------------17 1.6 幹細胞 (stem cell)及腫瘤幹細胞 [cancer stem cell (CSC)]----------------19 1.7 研究目的--------------------------------------------------------------------------------22 二. 材料與方法-------------------------------------------------------------------------------23 2.1漆酚的純化------------------------------------------------------------------------------23 2.2 細胞培養-------------------------------------------------------------------------------23 2.3 Topo II活性的測定--------------------------------------------------------------------24 2.4 兩階段Topo II活性測定--------------------------------------------------------------25 2.5 Topo II Electrophoretic Mobility Shift Assay (EMSA) ------------------------25 2.6 人類周邊血單核球細胞 (PBMC)的分離-----------------------------------------26 2.7 細胞活性測定--------------------------------------------------------------------------26 2.8 細胞粒線體膜電位的測定-----------------------------------------------------------27 2.9 細胞膜完整性的測定-----------------------------------------------------------------27 2.10. 細胞內DNA含量分析-------------------------------------------------------------27 2.11 DNA合成能力測定------------------------------------------------------------------28 2.12 細胞內Caspases活性的測定----------------------------------------------------28 2.13 細胞內RNA的萃取-----------------------------------------------------------------28 2.14 基因表現之微陣列晶片分析------------------------------------------------------29 2.15 反轉錄-聚合酵素連鎖反應--------------------------------------------------------30 2.16 Huh7細胞三度空間細胞培養-----------------------------------------------------30 2.17 TUNEL (TdT-mediated dUTP Nick-End Labeling) Assay------------------31 2.18 Hematoxylin – Eosin Y染色、DAPI染色及細胞表面抗原之免疫螢光染色----------------------------------------------------------------------------------------------------32 2.19 動物腫瘤實驗------------------------------------------------------------------------33 2.20 Rho 123染色及細胞分選----------------------------------------------------------34 2.21 小鼠血液抹片的製作---------------------------------------------------------------34 三. 結果-----------------------------------------------------------------------------------------35 3.1 天然漆漆酚的純化--------------------------------------------------------------------35 3.2 HQ17(3)抑制Topo II活性且為Topo II posion的藥物-------------------------35 3.3 HQ17(3)具有毒殺人類血癌細胞株HL-60與HL-60/MX2的效果而對不增生的PBMC則無影響-------------------------------------------------------------------------41 3.4 HQ17(3)具有抑制肝癌細胞株Huh7生長及DNA合成的效果---------------49 3.5 HQ17(3)處理引發Huh7細胞凋亡-------------------------------------------------52 3.6 HQ17(3)能於Huh7三度空間的培養系統中造成Huh7細胞DNA斷裂----60 3.7 HQ17(3)能夠於動物模式中抑制腫瘤生長及轉移------------------------------66 四. 討論-----------------------------------------------------------------------------------------71 五. 未來發展-----------------------------------------------------------------------------------75 5.1 由LLC細胞株分離出腫瘤幹細胞-----------------------------------------------------75 5.2 關於LLC中CSC之討論與未來之研究方向----------------------------------------79 六. 參考文獻-----------------------------------------------------------------------------------80 附錄: 建立抗原偵測及疫苗發展-----------------------------------------------------91 藥品清單--------------------------------------------------------------------------120 已發表之論文-------------------------------------------------------------------------------122 個人履歷表----------------------------------------------------------------------------------139 | |
| dc.language.iso | zh-TW | |
| dc.title | 天然物烷基對苯二酚作為抗癌藥物之研究 | zh_TW |
| dc.title | A study on botanical alkyl hydroquinones as anti-cancer drugs | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 邱義源,郭彥彬,謝森永,林亮音 | |
| dc.subject.keyword | 抗癌,烷基對苯二酚,拓樸異構脢II, | zh_TW |
| dc.subject.keyword | anti-cancer,alkyl hydroquinone,Topoisomerase II, | en |
| dc.relation.page | 141 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-01-23 | |
| 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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