臺灣博碩士論文加值系統

針對2-phenyl-4-quinolone (2-PQ)類緣化合物進行抗癌活性篩選，發現2-(2-fluorophenyl)-6,7-methylenedioxy-4-quinolone (K1)能有效的抑制多種人類癌細胞株生長，包括卵巢癌細胞株SKOV-3及乳癌細胞株MCF-7、MDA-MB-231等。於本研究中將探討K1之輻射增敏活性及其可能的分子作用機制。
K1會導致SKOV-3、MCF-7、MDA-MB-231的生長抑制，並成劑量反應關係，且對正常白血球細胞(PBMC)沒有明顯之細胞毒性，經由細胞群落生成法亦可發現K1能顯著的增加輻射增敏活性，又以SKOV-3細胞的敏感性最好。另外，利用流式細胞儀分析細胞週期，可發現合併K1及輻射後，能顯著的提高細胞停滯在G2/M期進而引起細胞凋亡，並且在併用二者後，能夠有效地抑制微管蛋白的聚合和干擾微管的組織，原因可能是透過活化CDK1/cyclin B1複合體及polo-like kinase 1而誘導細胞停滯於有絲分裂期的prophase到prometaphase之間，此種調控有絲分裂期相關蛋白質的方式，很可能是使K1產生輻射增敏效應的機制。總結來說，我們的結果顯示K1為一強效的抗有絲分裂劑，其活性亦能使卵巢癌細胞對於輻射更為敏感，在未來也具有相當大的潛力發展成輻射增敏劑，並於臨床上應用治療卵巢癌。

2-(2-Fluorophenyl)-6,7-methylenedioxy-4-quinolone (K1), a synthetic 2-phenyl-4-quinolone analog, was identified as a potent and selective antitumor agent in several human cancer cells, including breast cancer and ovarian cancer. The present study investigated the in vitro radiosensitizing effect of K1 and the underlying molecular mechanisms. K1 induced growth inhibition of ovarian cancer SKOV-3 cells and breast cancer MCF-7 and MDA-MB-231 cells in a concentration-dependent manner without overtly impairing the viability of normal cells (PBMC) obviously and enhanced SKOV-3 cells radiosensitivity by a SER of 2.5 when treated with 0.4 ?嵱 K1. In addition, co-treatment of K1 and radiation significantly induced G2/M phase arrest following by apoptosis, in contrast, pre-treatment of K1 24 h before radiation markedly increase sub-G1 phase. K1 could inhibit tubulin polymerization and disrupt microtubule organization. Moreover, the disruption of microtubule organization was significantly induced by co-treatment of K1 and radiation. Further western blot analysis indicated that K1 combined with radiation might cause cell cycle arrest at prophase progression to prometaphase by activating CDK1/cyclin B1 complex and polo-like kinase 1. This regulation of mitosis kinase was likely the mechanism underlying K1 induced cell radiosensitivity. Taken together, our data showed K1 exhibit a novel antimitotic antitumor activity which could strongly augment the response of ovarian carcinoma cells to radiation. K1 is a promising chemotherapeutic agent and can become a potent radiosensitizer worthy of further development into a clinical trial candidate for treating cancer, especially ovarian carcinoma.

目錄......................................................................................................I
圖目錄..................................................................................................III
表目錄..................................................................................................V
中文摘要..............................................................................................VI
英文摘要..............................................................................................VIII
縮寫表..................................................................................................X
第一章 緒論........................................................................................1
第一節 卵巢癌............................................................................1
第二節 輻射增敏合併療法........................................................6
第三節 細胞週期........................................................................13
第四節 化合物K1之研究概況...................................................22
第五節 研究動機與目的............................................................25
第二章實驗材料及方法......................................................................26
第一節 實驗材料........................................................................26
第二節 實驗方法........................................................................32
第三章 實驗結果................................................................................38
第一節 K1對人類癌症細胞株的影響.......................................38
第二節 評估K1對人類癌症細胞株的輻射增敏作用...............39
第三節 K1併用輻射對SKOV-3細胞週期之影響.....................41
第四節 K1併用輻射對微管蛋白之影響...................................44
第五節 K1併用輻射對細胞週期中G2/M期之相關蛋白質
表現的影響....................................................................46
第六節 K1併用輻射對細胞凋亡相關之蛋白質表現的影響..49
第四章 討論........................................................................................50
第五章 結論與展望............................................................................55
第六章 參考文獻................................................................................57
附圖......................................................................................................66

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