臺灣博碩士論文加值系統

根據衛生署民國九十二年癌症登記報告指出，口腔癌在臺灣十大癌症中死亡率與發生率皆位居第七位。 若單獨觀察男性， 此二率皆位居第四位。此外，口腔癌年增率是臺灣地區年增率第二高之癌症， 可見問題之嚴重。儘管近年在診斷及治療之科技上有不少進步，但傳統的外科手術、放射線療法和藥物化學療法都不甚令人滿意，整體來說，口腔癌病人之五年存活率並未有明顯改變 。因此，需要一個更好的治療方法來改善整體存活率及生活品質。 在第一章中我整理了目前應用在口腔癌的新穎分子治療(包含藥物及基因治療)方法。 而在基因治療方面包含載體的介紹，治療口腔癌的策略及臨床上的應用。 第二章中我們研究 p53正向細胞凋亡調控因子（p53 up-regulated modulator of apoptosis, PUMA）基因療法在口腔癌治療上的應用。 PUMA基因是調控細胞凋亡相當重要的基因，為p53 下游基因，不受p53弁鄍h活化所影響。 當PUMA被表現時，細胞會產生比p53 快速而且嚴重的細胞凋亡。 我們利用枝鏈型聚乙烯亞胺(branched polyethylenimine, PEI) 非病毒載體及PUMA基因 DNA 轉染口腔癌SAS細胞株。 我們發現以PEI轉染口腔癌細胞株SAS 的轉染率約為 40 %。 在SAS細胞株內大量表現外來的PUMA蛋白，會引起cytochome c 從粒腺體內釋放到細胞質中，接著去活化caspase-9, caspase-3 和 PARP，最後引起細胞 凋亡。 動物實驗發現，利用PEI當載體把PUMA 基因的DNA 打到老鼠口腔癌細胞株SAS引起的腫瘤，雖然不能讓腫瘤完全消失， 但經過四周後，老鼠身上的腫瘤和控制組比較，減少了 62.39 %。 初步證明 PUMA 基因對抑制口腔癌有相當好的效果。 此外由於釵h研究顯示，多藥物合併使用(Combined Therapy) ，或是基因治療及藥物合併使用可增加口腔癌病人之存活率。 因此在第三章我們建立四環黴素誘導 PUMA 基因表現系統 及 評估四種自然化合物(apigenin, berberine, resveratrol, gallic acid)對細胞生長的影響。 其中gallic acid 對 SAS 口腔癌細胞株24小時的半數抑制濃度（ID5O= 15.57±1.85 �嵱） 最低，且可造成 SAS 口腔癌細胞株的細胞凋亡 。但gallic acid對正常口腔黏膜細胞沒有毒性。 未來將持續研究，結合PUMA基因和藥物化學的複合式基因療法對口腔癌的治療成效。

Oral cancer is the fourth leading cause of cancer-related deaths in male population in Taiwan. Despite recent advances in radiotherapy and chemotherapy, the survival of patients with oral cancer has not improved significantly. As traditional treatments have not curbed this menace, many innovative approaches are being looked at for a cure. Recent studies have shown that polyethylenimine (PEI) nonviral vector is significantly more potent in cells bearing mitotic activity. This higher efficiency of gene transfer using PEI in proliferative cells, could reveal particularly interesting in heterogeneous tumor tissues, such as oral SCC tissue, containing both proliferating tumor cells and differentiated non proliferating stromal cells. Furthermore, PUMA (p53 upregulated modulator of apoptosis) was recently been found as an essential mediator of p53-dependent and -independent apoptosis in vivo. Therefore, we used PEI nonviral vector to transfer PUMA gene DNA into oral cancer cells for gene therapy on oral cancer. Firstly, we found the endogenous p53 in SAS cells could activate the PUMA promoter. The exogenous PUMA protein in SAS cells could induce apoptosis through the mitochondrial pathway. PUMA protein expression results in cytochome c release from mitochondria to cytoplasm, thereby activating caspases-9, caspase-3 and PARP. Furthermore, we found animals treated with PEI/wild-type PUMA DNA have significantly reduction in tumor size when compared with those treated with PEI/mutant DNA controls (p <0.05).
PUMA would be an ideal candidate tumor suppressor gene for oral cancer gene therapy. Our results suggest that PEI-mediated PUMA gene transfer is also a good candidate for adjuvant therapy with radiation or chemotherapy.
It has been shown that the antitumoral efficacy with gene therapy plus standard chemotherapeutic agents was significantly greater than with either agent alone. In the second part of study, we evaluated two standard chemotherapeutic agents (cisplatin, 5-FU) and four flavonoids (apigenin, berberine, resveratrol, gallic acid) for their effects on cell growth. Among the flavonoids, gallic acid is the most effective in inducing cell growth inhibition (ID50 =15.75 �嵱 at 24hrs) and showed differential cytotoxicity to SAS and normal oral mucosal cells. Therefore, gallic acid may be of value in treating oral cancers. Future studies are needed for the effects of gallic acid and PUMA-mediated gene therapy on the combined chemo/gene-therapy of oral cancer.

Abbreviationa 2
Abstract in English 3
Abstract in Chinese 5
Contents 7

Chapter 1 General Introductions 9
1.1 Introduction 10
1.2 Specific Aims 31
1.3 References 32

Chapter 2 PUMA Induce Apoptosis in vitro and in vivo. 43

2.1 Abstract 44
2.2 Materials and Methods 45
2.3 Results 51
2.4 Discussion 55
2.5 References 59
2.6 Figures 61
2.7 Figure Legends 72

Chapter 3 Development of New Combined Therapeutic Strategy to Treat Oral Cancer- A pilot study. 77

3.1 Abstract 78
3.2 Introduction 79
3.3 Materials and Methods 82
3.4 Results 84
3.5 Discussion 86
3.6 References 88
3.7 Figures 90
3.8 Figure Legends 102

Chapter 4 Future Perspectives 106

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