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系統識別號 U0026-0608201119221000
論文名稱(中文) 以喹唑啉酮類緣物 MJ-66 作為有效治療惡性神經膠質瘤之藥物開發
論文名稱(英文) MJ-66, a quinazolinone analog, is a potent drug against malignant gliomas
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 99
學期 2
出版年 100
研究生(中文) 陳靖
研究生(英文) Ching Chen
學號 S26981042
學位類別 碩士
語文別 英文
論文頁數 71頁
口試委員 指導教授-簡伯武
口試委員-侯曼貞
口試委員-陳柏熹
中文關鍵字 惡性神經膠質瘤  喹唑啉酮類緣物  有絲分裂災變 
英文關鍵字 malignant glioma  quinazolinone analog  mitotic catastrophe 
學科別分類
中文摘要 惡性神經膠質瘤屬於中樞神經系統常見的惡性腫瘤,具有高度增生和侵略正常組織的能力,目前患有惡性神經膠質瘤之癌症病患,經過手術切除、放射線或化學治療的病患,仍有相當高的復發率,平均存活率不到一年,因此開發出有效對抗惡性神經膠質瘤的藥物顯得當務之急。喹唑啉酮生物鹼在先前研究已經發現對於胃癌跟肺癌具有良好的抗癌活性,然而關於喹唑啉酮類緣物在治療惡性神經膠瘤的研究及其引起的機制還尚未釐清。因此本實驗將探討喹唑啉酮類緣物 2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone (MJ-66) 對於惡性神經膠質瘤的抗癌作用,作為提供新的治療方法。首先 MTS assay 和 Trypan blue exclusion assay 評判出 MJ-66 具有抑制惡性神經膠質瘤細胞生長的能力,進一步以流式細胞儀分析 DNA 含量,發現 MJ-66 可以使惡性神經膠質瘤細胞的細胞週期先停留在G2/M 時期然後走向死亡,同時從免疫螢光染色的結果發現 MJ-66會造成惡性神經膠質瘤有多核巨細胞以及多對紡錘絲之特徵。西方墨點法的結果發現 MJ-66 會引起硫胱氨酸蛋白酶的活化以及造成 Cdk1 和 Cyclin B1 不正常表達,顯示 MJ-66 透過引起細胞不正常分裂後,走向有絲分裂災變,並伴隨細胞凋亡的發生。另外我們也發現 MJ-66 不會造成不分裂的細胞走向有絲分裂災變死亡。在動物模式也證實 MJ-66 可以抑制人類惡性神經膠質瘤的生長。從以上實驗可得知 MJ-66 誘發惡性神經膠質癌細胞以有絲分裂災變的形式死亡,希望這樣的發現可以提供未來在對抗惡性神經膠質瘤的治療方法之一。
英文摘要 Malignant gliomas are among the most devastating cancers as these tumors rapidly grow and invade the surrounding brain parenchyma. Despite recent advances in surgery, radiotherapy, and chemotherapy, the prognosis of patients diagnosed with malignant gliomas remains very poor. Therefore, the development of the new anti-malignant glioma drug is urgently needed. Quinazolinone analogs are the derivative of quinazolinone alkaloids that have been demonstrated the antitumor activity of quinazolinone analogs against stomach and lung cancers. However, the effects and mechanisms of quinazolinone analogs against malignant glioma remain unclear. In the present study, we found that 2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone (MJ-66), a synthetic quinazolinone analog, significantly induced glioma cell death that was accompanied by reduced cell viability and inhibited glioma cell growth. Immunofluorescence staining showed that the MJ-66-induced cell death was associated with multinucleated phenotype and multipolar spindles that are typical characteristics of mitotic catastrophe, a special case of apoptosis. The flow cytometry analyses revealed that MJ-66 caused glioma cell cycle arrest at G2/M phase and increased the proportion of polypoidy cells. Further, Western blotting indicated that cyclin B1 increased and caspase 3 activated in gliomas after treated with MJ-66. Human glioma xenograft animal model showed that MJ-66 inhibited tumor growth in vivo. Together these results suggest that MJ-66 inhibited malignant gliomas growth through inducing mitotic catastrophe by interference of G2/M cell cycle checkpoint which may open a new avenue for the treatment of malignant gliomas.
論文目次 中文摘要 (Abstract in Chinese)…………………………………………………..1
英文摘要 (Abstract in English)……………………………………………….…..3
誌謝 (Acknowledgement)………………………………………………….….…..5
目錄 (Content)……………..…………………………………………6
圖表索引 (Lists of Figures and Tables).…………………………………………..7
縮寫檢索表 (Abbreviations).…………………………………………………........9
Chapter 1: Introduction.……………………………………….…………………..11 Chapter 2: Specific Aims……………………………………………….……….....29
Chapter 3: Materials and Methods. …………………………………….……….…31
Chapter 4: Results…………………………………………………….……….…...40
Chapter 5: Discussion.…………………………………………….………...…….59
References…………………………………………………………………….…...65
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