2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644548摘要：蕾莎瓦（sorafenib）是目前治療肝癌唯一有效的藥物，然而大約 30％接受sorafenib 治療的病人，肝癌仍然繼續增長，即使起初受 sorafenib 控制的腫瘤，經過一段時間治療後，也會逐漸對 sorafenib 產生抗藥性。因此了解肝癌細胞對sorafenib 產生抗藥性的原因，進一步發展預測或減少抗藥性的方法，是改善sorafenib 治療效果的重要議題。 Sorafenib 要發揮抑制肝癌的效果，必須經由細胞表面的傳送子（transporter）將藥物送進細胞，其中最重要的傳送子包括 organic cation transporter-1 (OCT1)、organic anion transporter peptides OATP 1B3 (OATP8)及 multidrug-resistant protein (MRP) 家族，這些傳送子也參與了核磁共振造影(MRI) 顯影劑 gadoxetic acid (Gd-EOB-DTPA; Primovist® )被肝細胞吸收及排放的過程。因此我們推論：如果肝癌細胞表面的傳送子缺乏或異常，是造成 sorafenib 抗藥性重要的原因，那麼這些有抗藥性的腫瘤在 Gd-EOB-DTPA-enhanced MRI的肝膽相（hepatobiliary phase），應該呈現較低度的顯影。我們可以利用這個機制，以非侵入性的影像方法，預測肝癌對 sorafenib 的抗藥性。 為了證實以上假說，本研究計畫將利用不同具抗藥性的肝癌細胞株，釐清肝癌細胞的傳送子表現與 sorafenib 抗藥性的關係，並且以小鼠模型，觀察這些細胞所形成的腫瘤，在 Gd-EOB-DTPA-enhanced MRI檢查時的影像特徵，藉此發展可以預測藥物療效的影像標記。 <br> Abstract: Until now, Sorafenib is the only medication proved to be effective in the treatment of hepatocellular carcinoma (HCC). However, de novo and acquired resistance markedly reduce its efficacy. To improve the treatment outcomes, it is important to look for markers in selecting patients for sorafenib treatment, and find ways to reduce the resistance. To exhibit its anticancer activity, sorafenib has to enter the tumor cells with the help of transporters on the tumor cells. Low expression levels of transporters are related to drug resistance in some human cancers. Organic cation transporter-1 (OCT1)、organic anion transporter peptides OATP 1B3 (OATP8) and multidrug-resistant protein (MRP) family are the most important transporter in the hepatic uptake and efflux of sorafenib. These transporters also involved in the metabolism of gadoxetic acid (Gd-EOB-DTPA), which is a new hepatobiliary-specific contrast medium for MRI. Significant correlations have been found between the transporter expression and the signal intensity in the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. Through this mechanism, we hypothesis the expression level of the transporters is a key factor influencing the drug resistance of sorafenib. In addition, the enhancing pattern of Gd-EOB-DTPA-enhanced MRI can predict sorafenib resistance of HCC. In this study, we are going to establish several sorafenib resistant HCC cell lines. Correlation Gd-EOB-DTPA-enhanced MRI of the HCC xenograft formed by these cells will be performed. The enhancing pattern of the MRI will be correlated with the transporters expression level and sorafenib resistance. By this study, we aim to develop an image marker to predict the treatment efficacy of sorafenib.蕾莎瓦肝癌細胞傳送子Gadoxetic acid-enhanced 磁振造影sorafenibhepatocellular carcinomatransportergadoxetic acid-enhancedmagnetic resonance imaging