抗癌藥物mimosine衍生物的合成及其抗癌效果之研究

洪文俊
高雄醫學院
細胞癌化的過程中，p53抑癌基因的變異非常常見，此基因的缺損和癌細胞對化學治癌藥物的抗藥性有著密不可分的關係。許多化學治癌藥物會增加癌細胞p53基因的表現，進而誘導p21WAF1基因的表現來抑制癌細胞的增生並且引發癌細胞自然死亡(Apoptosis)。許多癌細胞其p53基因的功能缺損，所以添加化學治癌藥物並無法有效的促進p53與WAF-1基因的表現，也無法有效的抑制癌細胞的生長。近來的研究顯示mimosine，一種由銀合歡種子萃取出的植物特有的氨基酸，在很低濃度時便可以在乳癌細胞內不經由p53直接活化p21WAF-1基因的表現並有效抑制乳癌細胞的生長。我們實驗室先前的研究發現mimosine可以抑制肺癌細胞週期素D1的表現亦可促進肺癌及肝癌細胞週期素抑制蛋白p21WAF-1及p27KIP1的表現並有效抑制肝癌及肺癌的增生。此外我們進行活體動物實驗探討此氨基酸對裸鼠體內肝癌及肺癌細胞生長的影響，結果證實mimosine確實具有明顯的抗癌效果且無顯著的副作用發生。不過因為以前其他的實驗室的活體動物研究報告顯示高濃度的mimosine會造成生物毒性，長時間使用或是體內累積劑量過高，會產生明顯的副作用。本年度計畫我們希望藉由化學修飾的方法合成mimosine的衍生物，並測試這些衍生物對培養的肝癌及肺癌細胞與活體動物腫瘤生長的影響以尋求毒性更小而抗癌效果更佳的類似物以利未來臨床的使用。 
關鍵字：Mimosine，化學修飾, 抑癌基因，週期素，p21WAF1，p27KIP1

Study of the anti-cancer effect of chemical derivatives synthesized form mimsine

Wen-Chun Hung
School of Technology for Medical Sciences, Kaohsiung Medical College
Mutations of p53 tumor suppressor gene are frequently found in the process of carcinogenesis. Recent results also suggest a close relationship between the defect of p53 gene and the development of drug-resistance in tumor cells. Many anti-cancer drugs enhance p53 gene expression and then activate subsequent p21WAF1 gene expression. The p21WAF1 protein may inhibit cell proliferation and induce apoptosis in cancer cells. However, chemotherapeutic drugs could not increase the p53 and p21WAFl gene expression in p53 defect cancer cells and could not inhibit cell proliferation effectively in these cells. Recent observations demonstrated that mimosine, a plant specific amino acid extracted from the seeds of Leucaena Glauca Benth, could activate p21WAF1 gene expression independent of p53 at very low concentration in breast cancer cells. Our recent results demonstrated that mimosine inhibited cyclin D1 expression of lung cancer cells and enhanced expression of P21WAF-1 and P27KIP1 protein, and
關鍵字：Mimosine, chemical modification, tumor suppressor genes, cyclins, p21WAF1, p27KIP1