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| 題名: | ABT737合併imiquimod使用對胃癌細胞之抗腫瘤機制、效能及其臨床應用 |
| 作者: | 林肇堂(Jaw-Town Lin);吳俊穎(Chun-Ying Wu) |
| 貢獻者: | 公共衛生學院公共衛生學系 |
| 日期: | 2012-07-31 |
| 上傳時間: | 2012-06-15 11:48:27 (UTC+8) |
| 摘要: | 研究背景：胃癌是台灣常?的癌症，大多?的患者均在胃癌末期診斷，手術根除的機會 並?高，而傳統局部放射線照射以及化學治?通常?只能部分緩解而非完全的將癌細胞 清除。因此發展新穎的胃癌治?方式刻?容緩。Bcl-2 家族蛋白在調控腫瘤細胞對抗癌 藥物的敏感性扮演十分重要的角色。ABT737 即是為?抑制Bcl-2 家族中抗凋亡蛋白 Bcl-2、Bcl-xL 及Bcl-w 所發展出?的小分子抗癌藥物。口服的ABT737 衍生物，ABT263， 目前已進入?床試驗中。但是，非ABT737 標靶之Mcl-1 蛋白的高?表現卻常給予腫瘤 細胞有對抗 ABT737 的能?。在過去的研究中我們發現imiquimod，一種?床上使用的 ?鐸受體7 ?激劑，可藉由轉譯抑制??低Mcl-1 蛋白，並可同時誘發基底細胞癌細胞 自噬性死亡及細胞凋亡。我們認為imiquimod ?低Mcl-1 蛋白的特性將可互補於ABT737 處?過程中和抗ABT737 腫瘤細胞株中最常?的Mcl-1 蛋白高?表現。因此，imiquimod 及ABT737 合併處?可能會有協同毒?腫瘤細胞的效應。然而imiquimod 及ABT737 單 獨對胃癌細胞的抗腫瘤效果仍屬未知。本研究將藉由胃癌細胞株及活體動物模式?探討 imiquimod 及ABT737 單獨對胃癌細胞的生物效應；探討imiquimod 及ABT737 合併使 用是否有其協同效應；及研究?與其中的分子機制。經由本研究的執?我們將提供一個 新的、可?的胃癌治?策?，並藉由其分子機制的剖析給予未?發展其他腫瘤治?策? 的?考。
Gastric cancer remains a common disease with a dreary prognosis. Traditional chemotherapy and radiotherapy may be applied, but do not cure the disease. Thus, improvement of gastric cancer therapy will depend on novel therapeutic approaches. The Bcl-2 family is important in modulating sensitivity to anticancer drugs in many cancers. The BH3 mimetic ABT737 is a potent small molecule inhibitor of the anti-apoptotic proteins Bcl-2/Bcl-xL/Bcl-w. An orally available ABT737 analogue, ABT263, is under phase I clinical trail for small cell lung cancer and leukemia. However, ABT737 resistant cells increase levels of Mcl-1 proteins, which are not targeted by ABT737. In our previous study, we determined that imiquimod, a clinical used toll-like receptor 7 agonist, can rapidly down-regulate Mcl-1 protein levels by inhibiting translation, and simultaneously induce autophagic cell death and apoptosis in basal cell carcinoma cells. We hypothesize that down-regulates Mcl-1 protein expression by imiquimod may compensate the acquired ABT737 resistance which caused by Mcl-1 up-regulation in cancer cells with ABT737 treatment alone. Thus, the combination of sub-apoptotic concentration of imiquimod with ABT737 combination may result in synergistic induction of cell death in human cancer cells including gastric cancer. However, the anti-tumor effects of imiquimod and ABT737 in gastric cancer have never been addressed before. In this study, we will examine the biological effects of imiquimod and ABT737 on gastric cancer cell lines, determine whether ABT737 is synergistically effective in killing gastric cancer cells in combination with the imiquimod in vitro and in vivo, and further evaluated their molecular mechanisms of action. This study will provide promising therapeutic potential of targeting anti-apoptotic Bcl-2 family members in treating gastric cancers, and it will validate rational molecular approaches that target anti-apoptotic defenses when developing cancer treatments. |
| 顯示於類別: | [公共衛生學系暨碩博班] 研究計畫
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