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全合成化合物 2-Aziridin-1-yl-3-[(2-{2-[(3-aziridin-1-yl-1,4-dihydronaphthalen-2-yl)thio]ethoxy}ethyl)thio]naphthoquinone (AZ-1) 造成口腔癌細胞死亡機制之探討.

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  1. 全合成化合物2-Aziridin-1-yl-3-[(2-{2-[(3-aziridin-1-yl-1,4-dihydronaphthalen-2-yl)thio]ethoxy}ethyl)thio]naphthoquinone (AZ-1) 造成口腔癌細胞死亡機制之探討 • 已有研究指出aziridinylbezoquinone類化合物具有抗癌活性,而其中的aziridine結構可以烷基化DNA,抑制DNA複製。本論文所使用的全合成藥物AZ-1在結構上具有兩個aziridine環,並且是分別位於兩個用-(CH2)2-O-(CH2)2-架橋連接的naphthoquinone上。AZ-1對CT-5’細胞的LD50是0.8μM,隨著AZ-1劑量與反應時間的增加,而細胞毒性增加。本論文與已進入臨床試驗用藥AZQ比較,AZQ屬於aziridinylbenzoquinone類化合物,具有兩個aziridine環。由實驗結果發現AZQ對CT-5’細胞的LD50是50μM。發現和AZ-1有相似結構,但沒有aziridine環的BQ,其LD50是8μM。實驗結果發現當同時加入U0126與AZ-1時,可降低AZ-1對CT-5’細胞毒性。在Hoechst染色的實驗發現AZ-1濃度為2μM時,會有凋亡小體的出現。而AZ-1濃度在0.125μM ~ 1μM時,會使細胞停留在G2/M期,但當AZ-1濃度為2μM時,則有細胞凋亡的現象產生。p53蛋白表現會隨著AZ-1濃度增加而增加,在濃度2μM時,可增加69 %,但p21蛋白的表現則沒有變化。G2/M期相關的蛋白Cyclin B則約增加50 % 的表現,但Cdc2蛋白的表現並不會隨著AZ-1濃度的增加而有明顯的變化。推測AZ-1造成的口腔癌細胞CT-5’的死亡原因和p53蛋白有關,在濃度為1μM以下會使細胞停止在G2/M期,而當濃度在2μM時,則可以誘發細胞進行程式化死亡。

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