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研究生:林聖哲
研究生(外文):Sheng-Che Lin
論文名稱:反轉錄病毒攜帶自殺基因及免疫調節細胞素於原位腦腫瘤之抑癌作用
論文名稱(外文):Retrovirus mediated suicide gene therapy and cytokine modulated immunotherapy for orthotopic glioma
指導教授:戴建國戴建國引用關係
指導教授(外文):Chien-Kuo Tai
口試委員:蕭光明李文乾
口試委員(外文):Kuang-Ming HsiaoWen-Chien Lee
口試日期:2011/7/26
學位類別:碩士
校院名稱:國立中正大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:77
中文關鍵詞:基因治療胞嘧啶去胺酶尿嘧啶磷酸核糖轉移酶介白素-2干擾素-α硝基還原酶
外文關鍵詞:genetherapycytosine deaminasecytosine deaminase::uracil phosphoribosyltransferaseinterleukin-2interferon-αnitroreductase
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在癌症基因治療的發展中,常利用攜帶治療基因的病毒載體做為對抗腫瘤的工具以達成治療癌症的目的。其中以鼠科動物白血病病毒(murine leukemia virus)與長臂猿白血病病毒(gibbon ape leukemia virus)為基礎的可複製型反轉錄病毒(replication-competent retrovirus,RCR)做為傳送基因的載體時,被證實是具有高效率的基因傳遞、穩定且持續的基因表達以及高度的腫瘤選擇性。在本篇的研究中,我們嘗試透過自殺基因療法與免疫調節細胞素療法兩種策略,期望能找到治療腦瘤的新途徑。我們首先比較ACE(改造自amphotropic murine leukemia virus)、CEM(改造自ecotropic murine leukemia virus)以及GS(改造自gibbon ape leukemia virus)三種RCR載體在大鼠腦瘤細胞RG2間in vitro與in vivo的基因傳播比較,並發現GS載體具有較高傳遞基因的潛能。在自殺基因療法中,藉由MTS assay的方式我們觀察到cytosine deaminase::uracil phosphoribosyltransferase(CD::UPRT)展現較cytosine deaminase(CD)極為優異轉換5-FC的效率。僅管以RCR攜帶CD或CD::UPRT在促進動物的存活上並沒有顯著差異,但藉由H&E組織染色依然觀察到CD::UPRT組別有著腫瘤體積顯著縮小的現象。而另一自殺基因nitroreductase則在in vitro測試與大鼠皮下治療實驗皆展現相當不錯的腫瘤毒殺能力。另一方面,我們分別測試在過去文獻被證實具有活化及刺激免疫細胞生長以摧毀腫瘤的免疫調節激素「介白素-2(interleukin-2)」與「干擾素α(interferon-α)」。然而,在測試結果中介白素-2雖可造成腫瘤細胞的縮小,卻沒有如預期般的增進動物的存活與激活免疫細胞;而干擾素α藉由CTL assay也無觀察到免疫細胞對腫瘤的毒殺。總結而言,若可以投入更多的研究以了解免疫調節激素在活化免疫細胞及毒殺腫瘤所扮演的角色,或許在未來能結合自殺基因療法提供癌症基因療法的另一種選擇。
GS-based and MLV-based replication-competent retrovirus (RCR) vectors used for cancer gene therapy are previously proven to be effective, highly stable, tumor-selective, and persistent. In this investigation, we employed suicide gene therapy and cytokine modulated immunotherapy to treated glioma. First, we compared the gene transfer efficiency of the three replicating retroviral vectors, including ACE (modified from amphotropic murine leukemia virus), CEM (modified from ecotropic murine leukemia virus) and GS (modified from gibbon ape leukemia virus), carrying GFP or dsRed gene as marker, and found GS vector mediated the best spreading efficiency both in vitro and in vivo. In suicide gene therapy, we tested cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT)/5-FC and nitroreductase (NTR)/CB1954 systems both in vitro and in vivo. In in vitro test, transduction of CD:UPRT could induce more cell death after exposure of 5-FC in RG2 cells than transduction of CD alone. Although there was no significant difference between CD and CD::UPRT in improving animal survival, the group of CD::UPRT still showed greater tumor reduction than that of CD. The other combination NTR/CB1954 displayed excellent cell toxicity and effectively inhibited tumor growth in s.c model. In immune modulated gene therapy, we tested IL-2 and IFN-α, which both have been reported to activate and stimulate the growth of immune cells to destroy tumor. IL-2 was found to reduce tumor size in animal, however, it could not prolong animal survival or activate splenocyte. IFN-α was found not to promote cytotoxicity of splenocyte to destroy tumor cell. In conclusion, the functions of these cytokines need futher investigation for the use of immunotherapy as alternative for tumor gene therapy in the future.
中文摘要 I
Abstract II
命名表 III
目錄 IV
圖表目錄 VI
附錄 VI
1. 緒論 - 1 -
1.1 腦瘤 - 1 -
1.2 基因治療 - 2 -
1.3 複製型反轉錄病毒載體 - 4 -
1.3.1 反轉錄病毒介紹 - 4 -
1.3.2 複製型反轉錄病毒載體介紹 - 5 -
1.4 免疫調節細胞素 - 7 -
1.4.1 Inerleukin-2 - 7 -
1.4.2 Interferon-α - 7 -
1.5 自殺基因 - 8 -
1.5.1 Cytosine deaminase::Uracil phosphoribosyltransferase - 8 -
1.5.2 Nitroreductase - 9 -
1.6 T淋巴球 - 10 -
1.6.1 輔助型T淋巴球(Helper T lymphocyte) - 10 -
1.6.2 細胞毒性T淋巴球(Cytotoxic T lymphocyte) - 11 -
1.7 動機 - 12 -
2. 材料與方法 - 13 -
2.1 材料 - 13 -
2.1.1 細胞株 - 13 -
2.1.2 質體 - 14 -
2.1.3 Oligonucleotide - 15 -
2.1.4 RCR vector - 16 -
2.2 方法 - 16 -
2.2.1 細胞株及其培養 - 16 -
2.2.2 可複製型反轉錄病毒之製作 - 17 -
2.2.3 載體之轉染(Transfection) - 17 -
2.2.4 病毒載體感染效力測試(Viral titer) - 18 -
2.2.5 病毒載體傳播效率測試 - 19 -
2.2.6 病毒載體穩定性測試 - 19 -
2.2.7 細胞毒性及MTS - 20 -
2.2.8 西方墨點法(Western blot) - 21 -
2.2.9 In vivo 腫瘤之植入 - 22 -
2.2.10 In vivo 病毒載體傳播效率測試 - 23 -
2.2.11 大鼠治療效果測試 - 24 -
2.2.12 IL-2 cDNA之偵測 - 25 -
2.2.13 從大鼠脾臟分離Splenocytes - 26 -
2.2.14 Mixed lymphocyte reaction(MLR)分析 - 26 -
2.2.15 細胞毒性T淋巴球 (CTL) 分析 - 27 -
2.2.16 組織包埋與切片 - 27 -
2.2.17 H&E stain - 28 -
2.2.18 統計 - 28 -
3. 結果 - 29 -
3.1 病毒載體GS4-CD::UPRT之建構 - 29 -
3.2 病毒載體的傳播效率比較 - 29 -
3.2.1 In vitro 傳播比較 - 29 -
3.2.2 In vivo 傳播比較 - 30 -
3.3 In vitro病毒載體穩定性 - 30 -
3.4 自殺基因毒殺效果 - 31 -
3.5 NTR於大鼠異位腫瘤模式之治療效果 - 32 -
3.6 CD 與CD::UPRT 於大鼠原位腫瘤模式之治療效果 - 33 -
3.6.1 100mg/Kg與500mg/Kg 之5-FC投予 - 33 -
3.6.2 H&E stain 觀察腫瘤生長情形 - 34 -
3.7 探討原位腫瘤模式之大鼠免疫反應機制 - 35 -
3.7.1 IL-2 對免疫細胞及大鼠存活之影響 - 35 -
3.7.2 Interferon-α與免疫細胞 - 37 -
4. 討論 - 39 -
5. 參考資料 - 48 -

圖表目錄
圖 一、反轉錄病毒載體 - 56 -
圖 二、GS4-CD::UPRT之建構 - 57 -
圖 三、in vitro病毒傳播測試 - 58 -
圖 四、病毒載體於顱內腫瘤模式的傳播 - 59 -
圖 五、利用multiple cycle infections assay偵測GS4-CD::UPRT的穩定性 - 60 -
圖 六、以MTS assay比較不同自殺基因組合對RG2的毒殺性 - 61 -
圖 七、不同NTR表現比例的RG2皮下腫瘤經CB1954處理後的生長情形 - 62 -
圖 八、不同5-FC劑量之F344/NNarl大鼠顱內治療模式生存曲線 - 63 -
圖 九、以H&E stain觀察治療過程中腫瘤生長情形 - 64 -
圖 十、以IL-2治療大鼠顱內腫瘤之生存曲線與腫瘤大小 - 65 -
圖 十一、以流式細胞儀分析MLR assay經IL-2刺激後T細胞之增生與活化情形 - 66 -
圖 十二、以流式細胞儀分析CTL assay中經IFN-α刺激後之毒殺情形 - 68 -

附錄
附錄 一、5-FC經CD與UPRT轉換路徑示意圖 - 70 -
附錄 二、NTR轉換CB1954示意圖 - 70 -

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