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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 詹東榮 | |
| dc.contributor.author | Ching-ling Lin | en |
| dc.contributor.author | 林慶齡 | zh_TW |
| dc.date.accessioned | 2021-06-13T00:00:57Z | - |
| dc.date.available | 2007-08-01 | |
| dc.date.copyright | 2007-08-01 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-31 | |
| dc.identifier.citation | Goldman, B., Multidrug resistance: can new drugs help chemotherapy score against cancer? J Natl Cancer Inst, 2003. 95(4): p. 255-7.
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Amino Acids, 2000. 19(3-4): p. 667-85. 54. Fang, L., et al., Discovery of a daunorubicin analogue that exhibits potent antitumor activity and overcomes P-gp-mediated drug resistance. J Med Chem, 2006. 49(3): p. 932-41. 55. Choi, C.H., J.H. Kim, and S.H. Kim, Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR. Biochem Biophys Res Commun, 2004. 320(3): p. 672-9. 56. Krasznai, Z.T., et al., Paclitaxel modifies the accumulation of tumor-diagnostic tracers in different ways in P-glycoprotein-positive and negative cancer cells. Eur J Pharm Sci, 2006. 28(3): p. 249-56. 57. Shen, D.W., et al., Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins. J Biol Chem, 1986. 261(17): p. 7762-70. 58. Sietsma, H., R.J. Veldman, and J.W. Kok, The involvement of sphingolipids in multidrug resistance. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28092 | - |
| dc.description.abstract | 過度表現多重藥物抗藥性mdr1基因為癌症病患主要化療失敗的原因之一，mdr1基因產物為細胞膜上之轉運蛋白P-glycoprotein (P-gp)，此蛋白將化療藥物從腫瘤細胞中排出因此無法有效毒殺腫瘤細胞。本論文的研究目的為建立具有抗藥性的腫瘤細胞株及其小鼠腫瘤動物模式，以應用於抗藥性腫瘤之研究。大腸癌CT-26/WT細胞株逐漸式培養在doxorubicin (DOX)濃度由低至高(1 nM-1 μM或10 μM)後，稱此為CT-26/DOX1和CT-26/DOX10亞型細胞株，以MTT試驗測試細胞對化療藥物的抗藥性，結果顯示CT-26/DOX1細胞對於DOX的抵抗倍率(resistant index; RI)相較於CT-26/WT為90倍，對P-gp基質之化療藥物vincristine和etoposide的RI也高於CT-26/WT，而對非P-gp基質之化療藥物5-FU和methotrexate，其RI則與CT-26/WT相似。CT-26/DOX1細胞在mdr1a mRNA表現較CT-26/WT高，而其他抗藥性基因mdr1b和mrp1表現則無差異。在P-gp蛋白表現和功能方面，CT-26/DOX1和CT-26/DOX10細胞顯著高於CT-26/WT。將細胞皮下接種於小鼠，於CT-26/WT和CT-26/DOX1活體腫瘤大小約75-250 mm3時，給予三劑DOX化療，CT-26/DOX1腫瘤大小相較於CT-26/WT有極顯著較高，老鼠犧牲後萃取其腫瘤的RNA和蛋白質，CT-26/DOX1腫瘤之mdr1a mRNA表現高於CT-26/WT，mdr1b和mrp1 mRNA則無差異。CT-26/DOX1腫瘤的P-gp表現亦高於CT-26/WT。而CT-26/WT和CT-26/DOX1腫瘤的病理特徵皆屬高度侵犯性和異型性，且血管充份供應。綜合上述結果證實本研究已建立抗藥性大腸癌CT-26/DOX1和CT-26/DOX10的細胞模式以及CT-26/DOX1的實驗動物模式。此抗藥性活體模式以核醫影像和自體放射性顯影，利用示蹤劑99mTc-MIBI診斷P-gp功能並無法測得影像，99mTc-MIBI 在CT-26/WT和CT-26/DOX1腫瘤分布量極低，但腫瘤對18F-FDG的攝取則非常清晰，未來可嘗試利用其他示蹤劑如99mTc-tetrofosmin、18F-paclitaxel和11C-verapamil等以進行抗藥性活體動物的影像分析。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-13T00:00:57Z (GMT). No. of bitstreams: 1 ntu-96-R94629024-1.pdf: 2170743 bytes, checksum: 25360059cd8a09b84038e8d0abf8d4a4 (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 目錄
誌謝-------------------------------------------------------------------------------------------- Ⅰ 中文摘要-------------------------------------------------------------------------------------- Ⅱ Abstract --------------------------------------------------------------------------------------- Ⅲ 目錄-------------------------------------------------------------------------------------------- Ⅴ 圖次-------------------------------------------------------------------------------------------- Ⅸ 表次-------------------------------------------------------------------------------------------- ⅩⅠ 簡寫對照表----------------------------------------------------------------------------------- ⅩⅡ 第一章、前言與文獻探討------------------------------------------------------------------ 1 第一節、多重藥物抗藥性(multidrug resistance；MDR)----------------------------- 1 一、MDR在臨床扮演之角色---------------------------------------------------------- 1 二、P-gp的構造、功能、分布及造成MDR的機制--------------------------------- 2 第二節、抗藥性腫瘤的細胞模式和實驗動物模式---------------------------------- 5 一、抗藥性腫瘤的細胞模式----------------------------------------------------------- 5 二、抗藥性腫瘤的實驗動物模式----------------------------------------------------- 6 第三節、MDR抑制物(modulators；inhibitors) ---------------------------------------- 6 一、P-gp抑制物(modulators; inhibitors)在臨床上的療效評估------------------ 6 二、天然的P-gp modulators------------------------------------------------------------ 8 第四節、臨床上診斷P-gp的策略------------------------------------------------------- 10 一、傳統診斷MDR之方法------------------------------------------------------------ 10 二、非侵入性核子醫學影像技術----------------------------------------------------- 10 三、核醫影像偵測P-gp之功能------------------------------------------------------- 11 四、99mTc-MIBI在抗藥性腫瘤動物模式造影之研究---------------------------- 12 第五節、研究動機與目的---------------------------------------------------------------- 13 第二章、實驗材料與方法------------------------------------------------------------------ 14 第一節、藥品資料------------------------------------------------------------------------- 14 第二節、實驗方法------------------------------------------------------------------------- 15 一、細胞株及動物模式----------------------------------------------------------------- 15 二、建立抗藥性細胞株之流程-------------------------------------------------------- 15 三、利用MTT測定化療藥物對細胞之毒殺作用---------------------------------- 17 四、Trypan Blue染色比較CT-26/WT和CT-26/DOX1細胞株之生長曲線 17 五、Flow cytometry分析P-gp表現--------------------------------------------------- 18 六、以calcein-AM分析細胞P-gp功能---------------------------------------------- 18 七、以rhodamine123 (Rh123)分析細胞P-gp功能--------------------------------- 19 八、建立抗藥性CT-26腫瘤動物模式之流程-------------------------------------- 19 九、反轉錄-聚合酶鏈反應(RT-PCR)------------------------------------------------- 20 十、Western blot分析P-gp表現------------------------------------------------------- 23 十一、腫瘤組織之蘇木紫-伊紅(hematoxylin-eosin; H&E)染色----------------- 24 十二、腫瘤組織P-gp和血管之免疫組織化學(Immunohistochemistry；IHC)染色--------------------------------------------------------------------------------------- 26 十三、偵測99mTc-MIBI在腫瘤之分布----------------------------------------------- 27 Ι、閃爍攝影機(scintigraphy)活體偵測腫瘤分布------------------------------ 27 Ⅱ、自體放射性顯影(autoradiography)偵測腫瘤分步------------------------ 28 十四、利用PET活體影像18F-FDG在腫瘤之分布-------------------------------- 28 十五、數據統計分析-------------------------------------------------------------------- 29 第三章、實驗結果--------------------------------------------------------------------------- 30 第一節、探討抗藥性CT-26/DOX1及CT-26/DOX10細胞株之形態、生長速 度、抗化療藥物及抗藥性基因和蛋白表現------------------------------------------- 30 一、觀察CT-26/WT、CT-26/DOX1及CT-26/DOX10細胞之形態-------------- 30 二、CT-26/WT、CT-26/DOX1及CT-26/DOX10細胞之生長速度--------------- 30 三、DOX及其他化療藥物對CT-26/WT、CT-26/DOX1及CT-26/DOX1 n7細胞之毒殺作用------------------------------------------------------------------------ 30 四、分析CT-26/WT、CT-26/DOX1細胞抗藥性(MDR)基因mRNA之表現 31 五、分析CT-26/WT、CT-26/DOX1及CT-26/DOX10細胞之P-gp表現-------- 32 Ι、Western blot分析P-gp表現---------------------------------------------------- 32 Ⅱ、Flowcytometry分析P-gp表現------------------------------------------------- 32 六、分析CT-26/WT、CT-26/DOX1及CT-26/DOX10細胞之P-gp功能-------- 33 Ι、Calcein-AM分析P-gp功能----------------------------------------------------- 33 Ⅱ、Rh123分析P-gp功能----------------------------------------------------------- 33 第二節、探討動物模式下抗藥性腫瘤之生長、抗藥性基因之表現以及CT-26腫瘤之病理特性--------------------------------------------------------------------------- 44 ㄧ、給藥組及對照組老鼠之體重、腫瘤生長變化--------------------------------- 44 二、CT-26/WT、CT-26/DOX1活體腫瘤組織MDR基因之mRNA表現------- 44 三、H&E染色觀察CT-26/WT和CT-26/DOX1腫瘤之特性--------------------- 45 四、CT-26/WT、CT-26/DOX1活體腫瘤組織之P-gp表現---------------------- 45 Ι、Western blot----------------------------------------------------------------------- 45 Ⅱ、IHC染色法----------------------------------------------------------------------- 45 五、IHC染色觀察CT-26/WT和CT-26/DOX1腫瘤之血管分布---------------- 46 第三節、探討99mTc-MIBI和18F-FDG在此抗藥性腫瘤模式之研究-------------- 46 一、Scintigraphy偵測活體99mTc-MIBI在CT-26/WT和CT-26/DOX1腫瘤之分布------------------------------------------------------------------------------------ 46 二、自體放射性顯影(autoradiography)偵測99mTc-MIBI在CT-26/WT和CT-26/DOX1腫瘤之分布------------------------------------------------------------- 46 三、18F-FDG在活體腫瘤之分布------------------------------------------------------ 46 第四章、討論--------------------------------------------------------------------------------- 58 第一節、抗藥性腫瘤細胞的建立------------------------------------------------------- 58 第二節、抗藥性腫瘤的實驗動物模式建立------------------------------------------- 62 第三節、探討99mTc-MIBI和18F-FDG在此抗藥性腫瘤模式之研究-------------- 63 參考文獻-------------------------------------------------------------------------------------- 65 | |
| dc.language.iso | zh-TW | |
| dc.title | 抗藥性大腸癌細胞株及其小鼠腫瘤動物模式之建立 | zh_TW |
| dc.title | Establishment and Characterization of A Multidrug Resistant (MDR) Colon Carcinoma Cell line and MDR Tumor Model in BALB/c Mice | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 朱瑞民,魏孝萍,林中天 | |
| dc.subject.keyword | CT-26,doxorubicin,multidrug resistance,mdr1a,P-glycoprotein,99mTc-MIBI, | zh_TW |
| dc.relation.page | 69 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-07-31 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 獸醫學研究所 | zh_TW |
| 顯示於系所單位： | 獸醫學系 | |
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