大腸直腸癌為世界前三高致死率的癌症，早期診斷及前期病患使用輔助性化療，可達良好的治療效果；第三期和第四期患者的存活率則較低，主要原因來自於抗藥性所產生的復發。因此，抗藥性的發生對於治療大腸直腸癌是一大挑戰。抗藥性產生的機制非常複雜，其詳細原因尚不清楚。為瞭解大腸直腸癌抗藥性的分子機制，我們建立了Oxaliplatin抗藥性細胞株，並透過cDNA array分析，我們找到許多可能參與化療抗藥性的基因；將這些表現量改變的基因利用CMAP 及生物資訊分析軟體，找出可能逆轉這些相關基因表現的藥物，以及可能參與的細胞內訊息傳遞途徑。本論文利用老藥新用的概念，用這些藥物來處理化療抗藥性細胞株，可以回覆原本在抗藥性細胞株中表現量受到變化的基因，亦可成功的抑制抗藥性細胞株的生長。同時，我們也利用這些藥物，來進一步研究抗藥性發生的機制。我們的研究證實有些藥物確實可以有效抑制化療藥抗性大腸直腸癌的腫瘤形成，並增加他們對化療藥物的敏感性。

Chemoresistance is one of the major challenges for colorectal cancer (CRC) therapy and is associated with poor prognoses in CRC patients. In order to investigate the molecular mechanism and find the alternative therapeutic strategies, oxaliplatin-resistant cells were established; a cDNA microarray was used to identify the potential genes involved in chemoresistance and a connectivity map (CMAP) analysis was used to find the potential candidates that have the potential to reverse the expression of the genes involved in chemoresistant CRC cells. Our results indicated that the expression level of several important genes is changed in oxaliplatin-resistant cells, and some candidate drugs have the potential to reverse their expression. Importantly, these drugs can effectively inhibit the tumor growth in drug-resistant cells. Our study also found that the activation of mitogen activated protein kinase (MAPK) pathway is involved in oxaliplatin resistance.

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