2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648760摘要：膀胱癌是對放射線敏感的。不過相較於標準的膀胱根除手術，肌肉侵襲性膀胱癌病人若是接受放射為基礎的治療，其長期存活率低了約10%。傳統上含順鉑的化學治療是被用來當成放射增敏劑，但這樣的治療有許多廣為人知的毒性。因此我們有很強大的需求要找能夠增進膀胱癌放射治療效果，又不增加毒性的藥物。一個可以增進膀胱癌放射治療效果的合理方法，是使用抑制放射治療相關信息傳導路徑的標靶藥物。表皮生長因子受體(EGFR)是其中 最重要之一 最重要之一 最重要之一 最重要之一 最重要之一 。愈來愈多證據顯示：EGFR信息路徑是決定放射反應的重要決定因子，而它們的抑制劑有很好的臨床潛力。在這個研究 在這個研究 計畫中 計畫中 ，我將使用一個可以同時阻斷EGFR和HER2的酪胺酸激酶抑制劑，來增加膀胱癌 細胞 的放射敏 的放射敏 感度 。在前驅性研究中我展示了在體外及活體的老鼠膀胱癌模式中，afatinib都是一個有效的放射增敏劑。我也展示了afatinib抑制了放射活化的EGFR與HER2信息，並增加了細胞DNA傷害與凋亡。本計畫的特定目標：目標一：比較第一代和第二代的EGFR酪胺酸激酶抑制劑，當作放射增敏劑用在膀胱癌細胞的效果。初步的結果顯示：第二代的afatinib放射增敏的能力，對於抑制T24和NTUB1人類膀胱癌細胞株的繁殖和生存，是優於第一代的erlotinib。目標二：探討HER2在膀胱癌EGFR媒介的放射保護效果中扮演的角色。初步的結果顯示：有anti-HER2 shRNA轉染的T24細胞株，是比控制組的T24細胞株對於erlotinib的放射增敏效果有更好的加強作用。目標三：瞭解EGFR的基因突變是否會影響膀胱癌afatinib的放射增敏效果。我希望：這個研究的結果可以協助達成”增進膀胱癌放射治療效果，又不增加毒性”的目標。<br> Abstract: Urinary bladder cancer is radiosensitive. However, the long-term survival of patients receiving radiation-based therapy in muscle invasive bladder cancer is about 10% inferior to patients receiving standard radical cystectomy. Traditionally cisplatin-containing chemotherapy is used as radiosensitizer but it has many well-known toxicities. Therefore, there is a strong need for agents to enhance the radiation effect in urinary bladder cancer treatment while not increasing the toxicities.A reasonable way to enhance the outcome of radiotherapy is by concomitantly using agents that inhibit radiation-activated signaling pathways. Epidermal growth factor receptor (EGFR) is one of the most important. Evidences are accumulated to show that EGFR is important determinants of radioresponse and their inhibitors have good clinical potentials.In this project, I will use a I will use a I will use a I will use a I will use a tyrosine kinases inhibitor which can inhibitor which can inhibitor which can inhibitor which can inhibitor which can inhibitor which can block EGFR and HER2 simultaneously to increase the radiosensitizing effect in bladder cancer cells. In pilot study I demonstrate in vitro and in vivo that afatinib is an effective radiozensitizer in murine bladder cancer model. I also showed that radiation-activated EGFR and HER2 signaling were suppressed by afatinib with the enhanced DNA damage and apoptosis. For the specific aims:Aim 1: to compare the radiosensitizing effect of first and second generation EGFR tyrosine kinase inhibitors in urinary bladder cancer cells. The preliminary data showed that the radiosensitizing effect of afatinib (a second generation agent) is better than erlotinib (a first generation agent) inhibit the survival and proliferation of T24 and NTUB1 human bladder cancer cell lines.Aim 2: to explore the role of HER2 in EGFR-mediated radioprotection of urinary bladder cancer cells. The preliminary data showed that the radiosensitizing effect of T24 cells transfected with anti-HER2 shRNA was better than treated T24 cells transfected with scramble RNA when combined with EGFR inhibitor erlotinib.Aim 3: to understand whether EGFR mutation of urinary bladder cancer cells will influence radiosensitization by afatinib.I hope that the results of this study can help to meet the need to enhance the radiation effect in urinary bladder cancer treatment while not increasing the toxicities.