https://scholars.lib.ntu.edu.tw/handle/123456789/188188
標題: | 皮質類固醇影響上皮細胞癌生長及化學藥物敏感性機轉之研究並探討與癌細胞反應模式相關之分子分類(1/3) | 其他標題: | Studies on the mechanisms of glucocorticoids on the growth and drug sensitivity of carcinomas, and exploring relevant molecular classification(1/3) | 作者: | 鄭安理 | 關鍵字: | 皮質類固醇;癌細胞;化學藥物感受性;Glucocorticoids;Glucocorticoid receptor;Carcinoma;Cell growth;Chemosensitivity;Drug resistance | 公開日期: | 2003 | 出版社: | 臺北市:國立臺灣大學醫學院內科 | 摘要: | 皮質類固醇除本身對於某些血液腫瘤 具細胞毒性之外,也常與抗癌化學藥物併 用以治療因化學藥物引起之噁心、嘔吐及 過敏反應等副作用。雖然類固醇己被証實 可以影響多種細胞之重要訊息傳遞徑路, 其中有些與癌細胞抗藥性有關。然而我們 對類固醇類藥物對於與一般癌細胞生長以 及化學藥物感受性可能產生之影響仍所知 極少。釐清這個問題對臨床腫瘤治療將會有重要影響。我們隨機選擇了十四株癌細胞株有系統地進行研究以解答這個問題。Dexamethasone (DEX )被選為皮質類固醇代表藥物。我們發現:1. DEX 確實對癌細胞株(十四株之中的 七株)的生長以及化學藥物感受性有影 響。DEX 對癌細胞的影響呈現異質性而且似乎是彼此互斥的。DEX(0.01~1.0uM )抑制四株細胞的生長 (MCF-7 ,MCF/MXR1 ,MCF/TPT300 及HeLa 細胞),提高了一株細胞對cisplatin 的化學藥物感受性(SiHa),並 降低兩株細胞對cisplatin, doxorubicin, 5FU,及taxol 的化學藥物感受性(H460 及Hep3B)。2. 此影響是皮質類固醇受體—依賴性 的。因為DEX 只有在含有高濃度皮質 類固醇受體(≧2.1x10 4 /細胞)的七株細 胞才有影響。在其他七株不受DEX 影 響的細胞中,有五株細胞皮質類固醇受 體濃度範圍僅在2.0~5.7x10 3 /細胞之 間。而另二株含有高濃度皮質類固醇受 體但不受DEX 影響的細胞中(TW01, TW04),我們發現其皮質類固醇受體不 具有功能。 3. DEX 在SiHa 細胞所造成的化學藥物致 敏感效應與其對NF-kB 的調控有著高 度相關。透過轉殖含有dominant negative IkB 的plasmid 進入SIHa cells 中以抑制NFkB 活性,我們發現原 先DEX 提高SiHa 細胞對cisplatin 的 化學藥物感受性的現象消失。 4. 利用即時定量RT-PCR 測定十位乳癌病 患癌細胞檢體,我們發現在不同病人的 癌細胞中的皮質類固醇受體含量有高 有低。我們推測臨床上有一定比例之癌 細胞含有高濃度皮質類固醇受體,並可 能對DEX 有感受性。 Objectives: Glucocorticoids (GCs) are commonly co-administered with anti-cancer drugs such as cisplatin to prevent drug-induced allergic reaction, nausea, and vomiting. But little is known regarding the effects of GCs on the growth and chemosensitivity of common carcinomas cells. Methods: Fourteen carcinoma cell lines representing breast (MCF-7, MCF-7/MXR1, MCF-7/TPT300), gastric (AGS, N87,SNU1), lung (H460), cervical (SiHa, HeLa, Caski), liver (Hep3B, Hut7), and nasopharyngeal (NPC-TW01, NPC-TW04) cancer were selected to assess the effects of dexamethasone (DEX) on the cell growth and cisplatin chemosensitivity of common human cancers. Results: DEX had mutually exclusive effects on either growth or cisplatin sensitivity in 7 of the 14 cell lines. DEX inhibited cell growth of 4 (MCF-7, MCF-7/MXR1, MCF-7/TPT300, and HeLa), increased cisplatin cytotoxicity of one (SiHa), and decreased cisplatin cytotoxicity of 2 (H460 and Hep3B) cells lines. Although the effect of DEX on these carcinoma cells was unexpectedly diverse, it remained GC receptor (GCR) dependent. The GCR contents of the 7 cell lines affected by DEX were significantly higher than those of the other 7 cell lines unaffected by DEX (5.2 ±2.5 ×10 4 vs 1.3 ±1.4 ×10 4 , P=0.005).Only two DEX-unresponsive cell lines (NPC-TW01 and NPC-TW04) had GCR contents at the high range as those of the 7 DEX-responsive cell lines. On further examination, the function of the endogenous GCR of these two cell lines was found to be impaired. Further, transfection and expression of a vector encoding GCR to AGS, a GCR low-expressing and GC non-responsive cell line, increased its susceptibility to DEX manifested as an increased resistance toward cisplatin. The cytotoxicity-enhancing effect of GC in SiHa cells correlated well with its effect on abrogating the cisplatin-induced activation of NF-B. Expression of a dominant-negative truncated I B gene in SiHa cells completely abolished the cytotoxicity-enhancing effect of DEX. Conclusions: GCs may affect growth or chemosensitivity of carcinoma cells containing high concentration of functional GCR. Although the effects are heterogeneous and currently unpredictable , our data underscore the importance of clarifying the impact on tumor control by the co-administed GCs to carcinoma patients receiving chemotherapy. It is mandatory to identify the molecular and cellular markers that help predict the diverse effect of GCs on carcinoma cells. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/23587 | 其他識別: | 912314B002166 | Rights: | 國立臺灣大學醫學院內科 |
顯示於: | 醫學系 |
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912314B002166.pdf | 2.08 MB | Adobe PDF | 檢視/開啟 |
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