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研究生:楊閔翔
論文名稱:以C6神經膠瘤細胞為模式建立篩選分化誘導藥物之平台
論文名稱(外文):Establishment of a platform for screening and mechanistic study of differentiation-inducing agents from rat C6 glioma cells
指導教授:蘇瑀蘇瑀引用關係
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:54
中文關鍵詞:神經膠瘤細胞分化
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在二十多年前已發表用分化誘導藥物來治療癌症。而目前臨床上的唯一用藥:為口服RA(retinoic acid)治療急性前髓性白血病,其可以誘導白血球分化而達到治療的效果。而為了要去開發新的誘導分化藥物則我們需要一個適當的治癒疾病目標。而神經膠細胞瘤是一個很好的選擇不只是因為其利用手術放射治療化療的治療效果有限,也由於其治療後也極易復發,故選擇其當作治療的目標。
經由吳榮燦老師研究團隊從五靈脂中萃取出可以誘導C6 glioma cells分化的物質,而 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one (BPO) 即是一個可能具有分化效力的化合物。我們便探討其可能的作用機制,與其分化方向並利用裸鼠測試活體中抑制腫瘤細胞的效果。為瞭解其分化的走向,我們由BPO所處理過的細胞會表現大量的2-3-cyclic nucleotide 3-phosphohydrolase (CNP)但是其glial fibrillary acidic protein (GFAP)的量會相對下降。且在活體動物實驗中即使是低劑量5 mg/kg/day 的 BPO 也會有明顯的抑制腫瘤生長的效果。並由於RA為誘導C6 glioma分化為成熟的神經膠細胞瘤,而Sodium butyrate (NaB)會誘導其分化為星狀細胞(astrocyte),並且在適當濃度之下會抑制其生長,而當使用 NaB plus lovastatin、 RA plus lovastatin和BPO plus lovastatin也會有輔助其生長抑制的效果 ,而依其外型我們也看到其誘導分化的效果與單獨處理藥物時有明顯的增加。並且由實驗中證明組蛋白的過度乙醯化(hyperacetylation)似乎是寡突細胞(oligodendrocyte)成熟的必須步驟, 而用trichostatin A (TSA)這種新的組蛋白(histone)乙醯化的藥物也發現在濃度為時即可發現其有類似星狀細胞的分化。
為了建構快速篩選誘導分化藥物的系統,且避免遺珠之憾,我們架構了含有secreted alkaline phosphatase (SEAP) reporter gene其是由寡突細胞特異性蛋白myelin -proteolipid protein (PLP)的驅動子(promoter)來調空的穩定細胞株C6 MH 26,並利用SEAP來快速檢測,來判定其是否會有促分化的效果,並且使用RA與NaB時,發現其與其分化方向有一致性的表現,RA會誘導其分化而表現大量的SEAP而BPO, NaB和TSA則影響不大或有抑制的效果。而同時處理lovastatin與RA時則發現其會快速的達到分化。而最後我們的DATA中指出可以用TSA來當作一個藥物的先驅物(lead compound),並依此來設計可能的分化誘導藥物。
中文摘要…………………………………….2
英文摘要…………………………………….4
前言………………………………………….11
材料………………………………………….13
方法………………………………………….18
結果………………………………………….24
討論………………………………………….30
參考文獻…………………………………… 35
圖表
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