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研究生:王倩如
研究生(外文):Chien-Ju Wang
論文名稱:利用抗氧化劑改善pegylated liposomal doxorubicin (PLD)誘導之手足症候群及其協同抗癌效用
論文名稱(外文):Amelioration of pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome by antioxidants with synergistic anti-tumor effect
指導教授:何秀娥
口試委員:林山陽蔡義弘許明照謝堅銘
口試日期:2013-07-17
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥學院生技製藥產業碩士專班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:90
中文關鍵詞:艾黴素手足症候群活性氧類白藜蘆醇烏黎蘆醇薑黃素牛樟芝萃取物
外文關鍵詞:DoxorubicinHand-Foot SyndromeReactive Oxygen SpeciesResveratrolTetrahydroxystilbene glucosideCurcuminEthanol extraction of antrodia cinnamomea
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Pegylated liposomal doxorubicin (PLD)為doxorubicin以polyethylene glycol (PEG)修飾的微脂體包覆劑型常用於卵巢癌及乳癌的治療,相較於傳統的doxorubicin,PLD可以降低心臟毒性、增加藥物體內半衰期及迅速滲透腫瘤組織的效果,但由於PLD長時間的血液循環,會從肢端微血管滲出累積在手足部位細胞釋放出doxorubicin,在細胞內產生活性氧類(reactive species oxygen, ROS)增加氧化壓力引發細胞凋亡,導致嚴重的手足症候群副作用。
因此本研究目的在於探討是否能藉由抗氧化劑降低細胞內doxorubicin-induced ROS的產生來達到預防PLD所造成之手足症候群,同時也觀察抗氧化劑是否與doxorubicin具有協同作用增進患者在癌症治療上的效果。
本研究以白藜蘆醇、烏藜蘆醇、薑黃素以及牛樟芝萃取物四種抗氧化劑作為研究對象。實驗分為兩部分(一)以3T3纖維母細胞作為手足的正常細胞模式,評估這四種抗氧化劑在預防及降低PLD所造成之手足症候群的能力,(二)以MCF-7乳癌細胞模式探討抗氧化劑與doxorubicin的協同抗癌作用能力。實驗結果顯示,在投予doxorubicin前事先投予白藜蘆醇,對3T3纖維母細胞有最佳的抗氧化作用其次為薑黃素,顯示此二種抗氧化劑具有預防手足症候群產生的效果。若將抗氧化劑與doxorubicin同時投予則以牛樟芝萃取物的抑制doxorubicin-induced ROS之效果最佳,具有可降低副作用產生之效果。此外,白藜蘆醇及薑黃素與doxorubicin一起投予MCF-7乳癌細胞時比單獨使用doxorubicin更能降低癌細胞存活率,顯示白藜蘆醇和薑黃素對doxorubicin的抗癌效果具有協同作用。
Pegylated liposomal doxorubicin (PLD) was formulated by the polyethylene glycol-modified liposome that coated drug doxorubicin and often used on breast and ovarian cancer. PLD could reduce the cardiac toxicity, increase half-life and target to tumor tissue versus to traditional doxorubicin. But easily induced hand-foot syndrome (HFS) since prolonged circulation of PLD leading extravasation from microvascular to extremities and accumulate in those tissue and release doxorubicin. Doxorubicin produces reactive oxygen species that induced aberrant cell and progressively leading to cell apoptosis.
Therefore, the aim of this study was to investigate whether antioxidants have abilities on reducing doxorubicin-induced ROS and synergistic anti-cancer effect with doxorubicin that could prevent hand-foot syndrome and enhance the efficacy of cancer treatment.
In this study, we choose reseratrol, tetrahydroxystilbene glucoside, curcumin and extraction of antrodia cinnamomea as experimental subjects. The experiment divide into two parts: (1) 3T3 fibroblast cell was a normal cell model to evaluate to antioxidant ability of four antioxidants on preventing and reducing HFS. (2) The synergistic anti-cancer effect of antioxidants with doxorubicin on MCF-7 breast cancer model was evaluated.
The results showed that pretreated resveratrol was the best antioxidant on protecting cell from ROS and curcumin was second one. If cotreated extraction of antrodia cinnamomea with doxorubicin could inhibit doxorubicin-induced ROS. Therefore, Resveratrol and curcumin increased cell antioxidant ability by improving activity of superoxide dismutase. Additionally, resveratrol and curcumin had synergistic effect with doxorubicin on MCF-7 breast cancer. According to these results, resveratrol and curcumin have potentials of being clinically applicable to prevent hand-foot syndrome and enhance the doxorubicin anti-cancer efficiency.
目錄 I
附表目錄 V
附圖目錄 VI
中文摘要 IX
Abstract XI
壹、緒論 1
第一節 研究背景介紹 1
一、Doxorubicin (DOX)之作用機制及其優缺點 1
(一)Doxorubicin之作用機制 1
(二)Doxorubicin之優缺點 2
二、Pegylated liposomal doxorubicin之優缺點 4
三、手足症候群(Hand-foot syndrome, HFS)的分級及治療 9
(一)手足症候群之介紹 9
(二)手足症候群的分級與劑量調整 9
(三)目前對於手足症候群的預防 10
四、Pegylated liposomal doxorubicin (PLD)誘導之手足症候群發生 10
(一)PLD誘導手足症候群之原因 10
(二)PLD誘導手足症候群之機制 14
五、抗氧化劑之應用 18
(一)白藜蘆醇 ( Trans-3,5,4''-trihydroxystilbene, resveratrol, RSVL) 18
(二)烏黎蘆醇 ( tetrahydroxystilbene glucopyranoside, THSG) 19
(三)薑黃素 (Curcumin) 20
(四)牛樟芝萃取物 (Antrodia cinnamomea) 21
第二節 研究動機與目的 21
貳、實驗材料與方法 23
第一節 實驗材料 23
一、細胞株 23
二、試劑藥品 23
三、套裝實驗組 24
第二節 儀器設備 24
第三節 實驗方法 25
一、牛樟芝萃取 (Extraction of Antrodia cinnamomea) 25
二、細胞株培養 26
(一)3T3 fibroblast cell 26
(二)MCF-7 breast cancer cell 27
三、實驗設計流程圖 27
四、細胞存活率測定(3T3 fibroblast cell viability) 30
五、細胞內ROS測定 32
(一)預處理(pretreatment) 33
(二)共同處理(cotreatment) 33
六、細胞核螢光染色 34
七、粒線體內超氧化物螢光染色 35
八、超氧化物歧化酶活性測定( SOD activity assay) 36
九、抗氧化劑協同抗癌效果之評估 38
叁、結果與結論 41
第一節 牛樟芝萃取物UPLC定性分析 41
第二節 不同抗氧化劑對3T3 fibroblast cell細胞存活率評估 41
一、溶劑對細胞存活率之影響測定 42
二、白藜蘆醇 (Resveratrol, RSVL) 43
三、烏黎蘆醇 (Tetrahydroxystilbene glucoside,THSG) 44
四、薑黃素 (Curcumin) 45
五、牛樟芝萃取物 (extraction of Antrodia cinnamomea , EEAC) 45
第三節 抗氧化劑之抗氧化能力評估:3T3 fibroblast cell細胞內ROS測定 48
一、抗氧化劑預處理 ( pretreatment ) 48
(一) 白藜蘆醇 (Resveratrol, RSVL) 49
(二) 烏黎蘆醇 (Tetrahydroxystilbene glucoside,THSG) 49
(三) 薑黃素 (Curcumin) 50
(四) 牛樟芝萃取物 (EEAC) 50
二、抗氧化劑共同處理 ( cotreatment ) 53
(一) 白藜蘆醇 (Resveratrol, RSVL) 53
(二) 烏黎蘆醇 (Tetrahydroxystilbene glucoside,THSG) 54
(三) 薑黃素 (Curcumin) 54
(四) 牛樟芝萃取物(EEAC) 55
三、四個抗氧化劑(RSVL、THSG、curcumin及EEAC) 抗氧化能力綜合比較 57
第四節 抗氧化劑之抗氧化能力評估:3T3 fibroblast cell粒線體內超氧化物及細胞核染色測定 57
第五節 抗氧化劑之抗氧化能力評估:3T3 fibroblast cell細胞內超氧化物歧化酶活性測定 65
第六節 抗氧化劑及doxorubicin對乳癌細胞MCF-7協同作用之評估 66
肆、結論 70
伍、參考文獻 71
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