2011-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644619摘要：肺癌是目前全世界癌症死亡的主因之一，台灣也不例外，死亡率的增加在台灣更是驚人。肺癌的早期診斷有其困難，主要的原因是初期的肺癌不易有症狀，而且容易早期轉移。因為這個緣故，在台灣非小細胞肺癌的病人，只有不到三分之一的病人能開刀。因此，全身性的治療，包括化療的角色變的很重要，不論是晚期的病人或是術後的病人為了可能的微小轉移。在肺癌的化學治療從晚期的傳統化療，手術前的化療或是手術後的化療合併，順鉑（cisplatin）的雙重藥物化療仍為主流。但是只有30至40百分比的病人，對於這樣的化療有反應。有部份的病人不僅沒有反應，反而承受了化療的副作用。因此，事先找出對含順鉑治療有反應的病人，能減少不必要的副作用。現今的研究發現修復DNA的基因，包括ERCC1、BRCA1都可以用來預測化療的反應。我們有興趣的是，是否有其他更好的標記可以預測順鉑化療的反應。比較對順鉑有反應或無反應的病人組織之基因表現（利用微陣列技術）是可行但不容易實施，主要是檢體不容易拿到。在肺癌晚期接受化療的病人，通常不會取大量的組織，因此不適合做微陣列分析。而肺癌早期接受開刀的病人，又無法判斷是否為順鉑抗藥。唯一能拿到足夠組織，又能判斷是否為藥物敏感或抗藥只有在stage IIIA 術前接受化療的病人。肺癌組織內的DNA及RNA會被抽取，根據化療的反應分成敏感及抗藥兩組。利用cDNA微陣列、甚至microRNA array，比較這兩組的差異，找出可能與順鉑抗藥性有關的基因。接著利用一群病人化療前的組織切片，及肺癌晚期的病人接受過含順鉑的化療前的切片，來證實我們找到的基因，的確與順鉑的抗藥性有關。同時我們也要研究已證實的DNA修復基因，包括ERCC1、ERCC2、XRCC1、XRCC2、BRCA1、RRM1在這兩群病人的表現及預後。ERCC1基因多型性也是我們的研究之一。最後我們會研究找到的基因其抗藥的機轉，藉由基因的屬性或利用cDNA microarray做分析，找出可能的方向進一步研究。本研究的目的是想找到與ERCC1一樣好或更好的標記，來預測化療的反應，以提高存活率。<br> Abstract: Lung cancer is the leading cause of death around the world including Taiwan and the mortality rate increases rapidly in recent years. It is difficult for early detection of lung cancer because of little symptoms at the beginning and easily metastases. Less than one third of patients with non-small cell lung cancer received operation in Taiwan. Systemic therapies including chemotherapy become important for extend survival in advanced stages and even in early stages for micrometastases. No matter in traditional chemotherapy for the advanced disease, neoadjuvant or post-operation adjuvant chemotherapy, cispaltin-based doublets chemotherapy remains the standard. But only 30~40% patients had moderately effective response to chemotherapy. On the contrary, some patients suffer adverse effects without benefit. It becomes important to predict likely responders before chemotherapy. DNA repair genes like ERCC1 and BRCA1 are now proved to be reliable predictors for cisplatin-based chemotherapy. We are interesting that are there any other predictors for cisplatin-based chemotherapy. Comparison of transcriptome profilings between chemoresistance and chemosensitive from clinical specimens is difficult, because the biopsy samples are small in advanced disease or cannot define as chemoresistance or chemosensitve in post-op patients without chemotherapy. Only in the patients with stage IIIA disease who receive neoadjuvant chemotherapy followed by operation, we can get adequate tissues and adequate information. We can define the patients with chemoresistance or chemosensitive by response to chemotherapy. DNA and RNA will be extracted in post-operation frozen tissue stocks. cDNA microarray, or even micro RNA array will be done and compared. Drug resistance and sensitive cancer cell lines will also be tested and compared. We hope to find chemoresistance related genes and then validate by pre-neoadjuvant biopsy samples from the same group as well as patients with advanced disease who received cisplatin-based chemotherapy. These identified genes as well as DNA repair genes such as ERCC1, ERCC2, XRCC1, XRCC3, BRCA1 and RRM1 will be tested and correlated with clinical outcomes. Polymorphism of candidate genes will also be tested. Mechanism of chemoresistnace from identified genes will be further elucidated by functional assay. We hope to find a predictor as good as or better than ERCC1 for cisplatin resistance and could provide a customized chemotherapy with better survival in the future.肺癌化療抗藥性腫瘤幹細胞lung cancerdrug resistancechemotherapycancer stem cells.