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研究生:蘇富敏
研究生(外文):Fu-Min Su
論文名稱:沙利竇邁抗肝癌之基礎與臨床研究
論文名稱(外文):The Basic Study and Clinical Effect of Thalidomide on Hepatocellular Carcinoma
指導教授:蔡東榮蔡東榮引用關係
指導教授(外文):Tong-Rong Tsai
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:藥學研究所碩士在職專班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:52
中文關鍵詞:肝癌沙利竇邁
外文關鍵詞:ThalidomideHepatocellular carcinoma
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台灣地區為B型肝炎病毒感染之盛行區。慢型B型肝炎病毒感染會導致慢型肝臟疾病及肝細胞癌。由於缺乏治療的肝癌病人將快速面臨死亡,而接受治療的肝癌病人又常因肝癌再發而預後不佳。因此,尋找有效的治療方法並了解其機轉,顯得十分重要。沙利竇邁(Thalidomide)已有報告指出可以控制肝癌惡化,所以探討沙利竇邁治療肝癌機轉是相當具有臨床價值。故本研究分成基礎與臨床二部份來探討。基礎部份之目的乃以沙利竇邁探索其抗肝癌可能的機轉。本實驗假設沙利竇邁具有肝癌細胞毒殺效果,因此以數種肝癌細胞株(HepG2、Hep3B、PLC/PRF/5)加入不同濃度沙利竇邁(1 �慊/ml、3 �慊 /ml、10 �慊 /ml、30 �慊 /ml、100 �慊 /ml),經XTT呈色反應,以ELISA Reader分光光度計,來探討沙利竇邁抑制癌細胞增生狀況並確認藥物濃度和作用時間與細胞毒殺效應間的相關性。實驗結果與預期的結果相反,沙利竇邁劑量高達100 �慊 /ml仍未發現能有效地抑制肝癌細胞增生作用。因此推翻本實驗假設,沙利竇邁不具有肝癌細胞毒殺效果。間接證明沙利竇邁可能是經由免疫調節作用或經由抑制血管新生作用而非細胞毒殺作用來抑制肝癌細胞增生。臨床部份之目的為探討影響口服沙利竇邁治療肝癌效果的因子,因此以回溯性實驗設計,收集整理所有使用口服沙利竇邁肝癌患者資料進行分析。結果發現只有11.6%接受沙利竇邁治療的肝癌病人腫瘤縮小,但沙利竇邁治療可延長病人的存活日數。性別、年齡、肝疾病組織病理狀態、Child-Turcotte-Pugh 分類、肝癌對沙利竇邁治療反應情形等對病人存活日數並無任何的影響。但肝癌Okuda分期第二期及第三期病人接受沙利竇邁治療的存活時間顯著比文獻上不治療的對照組存活更久。病人於沙利竇邁治療前至少曾接受一次經動脈化療栓塞(TACE)者,比完全未曾接受TACE者,其存活天數顯著增加。以危險率比(Risk Ratio)評估,沙利竇邁治療前接受至少一次TACE治療的影響最大,其次為Okuda分期。肝癌對沙利竇邁治療反應情形對病人的存活日數並無任何的影響,這是因為沙利竇邁缺少直接毒殺肝癌細胞的作用而無法造成腫瘤縮小,因此無法改變Okuda分期而影響病人存活日數。接受沙利竇邁治療的肝癌病人,其死因最常見為感染症併發敗血症,因此沙利竇邁治療而延長病人存活日數的效果也可能被感染造成死亡所抵銷。
著者研究結論為沙利竇邁缺少直接毒殺肝癌細胞的作用,因此無法縮小腫瘤,但治療可延長病人的存活日數,且因為不良藥物反應十分輕微,所以可以一試,但仍應注意其他較嚴重的不良藥物反應及感染造成的併發症。
Hepatitis B virus (HBV) infection is endemic in Taiwan. Chronic HBV infection can lead to chronic hepatitis, liver cirrhosis and Hepatocellular carcinoma (HCC). The natural history of HCC without treatment is quickly fatal. There are limited therapeutic modalities for HCC up to date. The prognosis is further worsened by the frequent recurrence. Thalidomide was reported to control the progression of terminal HCC. Therefore, understanding its efficacy and mechanism would be important to apply thalidomide to manage HCC.
The first part, we supposed that thalidomide exerted its effect on HCC by the cytotoxic activity. Three different hepatocellular carcinoma cell line, namely HepG2、Hep3B、PLC/PRF/5, were tested with Thalidomide ( 1 �慊/ml、3 �慊/ml、10 �慊/ml、30 �慊/ml、100 �慊 /ml). The cytotoxic effect was indirectly evaluated by XTT colorimetric assay. The result was somewhat surprising that thalidomide did not have any direct cytotoxic effect on HCC cell lines up to the concentration of 100 �慊 /ml. Therefore, we concluded that thalidomide did not exert its anti-HCC activity by the direct cytotoxicity. This result might indirectly support its antineoplastic mechanisms by immuno-modulation or anti-angiogenesis.
The second part, we investigated the efficacy of thalidomide against HCC and its variables. Retrospectively, we collected the clinical characteristics of patients who received thalidomide as a salvage therapy against HCC. Totally 69 patients were included. We found that only 11.6 % (8/69) of patients had partial response. Age, gender, hepatic disease state, Child-Turcotte-Pugh classification, thalidomide response, and etiology related to HCC did not affect the survival days of patients. Patients of Okuda stage I (median survival of 148 days) or stage II (median survival of 132 days) had longer survival than Okuda stage III (median survival of 63 days) (p= 0.0133). Okuda stage III had higher mortality than stage II (risk ratio 2.6; 95% CI: 1.28-5.05). Patients receiving previous transarterial chemoembolization (TACE) before thalidomide therapy had better survival (p=0.0013) than receiving other modalities (risk ratio 2.9; 95% CI: 1.78-4.61). There was a high sepsis-related death (42.0%; 29/69) in patients receiving thalidomide.
In conclusion, thalidomide did not possess the direct cytotoxic activity against HCC to decrease the tumor size. However, it could prolong the survival days. The adverse drug reaction was mild. Therefore, thalidomide could be a salvage therapy to patients with terminal HCC. Nevertheless, infection should be monitored.
目錄 Ⅰ
表次目錄 Ⅴ
圖次目錄 Ⅵ
中文摘要 Ⅶ
英文摘要 Ⅹ
壹、緒論
一、 前言 1
二、 肝癌臨床表徵與診斷 2
三、 肝癌治療病程 2
四、 沙利竇邁(Thalidomide)與肝癌 3

貳、研究材料與方法
第一章、沙利竇邁對肝癌細胞株之毒殺效應 8
一、研究材料及方法
(一)、實驗材料 9
(二)、儀器 10
(三)、實驗方法與步驟
1、各種培養液及試劑之詳細配製方法 11
2. 細胞培養相關實驗方法 14
3.實驗方法
(1)細胞培養 18
(2)實驗步驟 18
(3)細胞增生抑制作用分析 19
4.統計方法 19
第二章、影響口服沙利竇邁治療肝癌病患臨床療效的因子分析
二、研究材料及方法
(一)、研究對象與實驗設計 20
(二)、統計方法 23

參、研究結果
一、細胞增生抑制作用之影響 26
二、肝癌病人基本資料分布情形
(一)、性別分布情形 35
(二)、年齡分布情形 35
(三)、肝疾病組織病理分布情形 35
(四)、肝疾病病因分布情形 35
(五)、肝癌Okuda分期分布情形 36
(六)、肝功能child-Turcotte-Pugh分布情形 36
(七)、沙利竇邁治療前是否曾接受TACE治療 36
(八)、病人存活日數分布情形 36
(九)、病人對沙利竇邁治療反應分布情形 37
(十)、服藥順從性 38
(十一)、沙利竇邁治療之不良藥物反應 38
(十二) 、�悜L兒蛋白數值 38
(十三)、死亡原因 39
(十四)、影響病人存活日數因子分析 39
1、性別對病人存活日數的影響 39
2、年齡分組對病人存活日數的影響 40
3、肝疾病組織病理對病人存活日數的影響 40
4、肝疾病病因對病人存活日數的影響 41
5、肝癌Okuda分期對病人存活日數的影響 41
6、 Child-Turcotte-Pugh 分類對病人存活日數的影響 42
7、沙利竇邁治療前接受至少一次TACE治療對病人存活
日數的影響 43
8、沙利竇邁治療反應情形對病人存活日數的影響 43
9、Cox proportional hazard model處理多個因子影響下的
生存曲線,並檢定沙利竇邁治療對病人存活日數的影響 44
(十五)、影響病人對沙利竇邁治療反應因子分析 45

肆、討論 46
一、沙利竇邁(Thalidomide)的作用機轉 49
二、沙利竇邁目前臨床主要的應用治療 54
三、沙利竇邁的不良藥物反應 58
四、沙利竇邁治療肝癌病患的臨床療效 60

伍、結論 63
陸、參考文獻 65

表次目錄

表一、肝癌Okuda臨床分期 2
表二、肝硬化之分級 :Child-Turcotte-Pugh 計點系統 22
表三、沙利竇邁治療肝癌的臨床藥物使用評估表 24
表四、沙利竇邁的各種作用及機轉 38


圖次目錄

圖一、沙利竇邁的結構式 5
圖二、沙利竇邁經由P450酵素的代謝 6
圖三、沙利竇邁與5-FU對PLC Cell的細胞毒殺效果 26
圖四、沙利竇邁與5-FU 對Hep G2 Cell的細胞毒殺效果 27
圖五、沙利竇邁與5-FU對Hep 3B Cell的細胞毒殺效果 28
圖六、肝癌病人性別分布情形 29
圖七、肝癌病人年齡分布情形 29
圖八、肝癌病人肝疾病組織病理分布情形 29
圖九、肝癌病人肝疾病病因分布情形 29
圖十、肝癌病人Okuda分期分布情形 30
圖十一、肝癌病人肝功能child-Turcotte-Pugh計分分布情形 30
圖十二、肝癌病人沙利竇邁治療前是否曾接受TACE治療 30
圖十三、肝癌病人病人存活日數分布情形 30
圖十四、肝癌病人對沙利竇邁治療反應分布情形 31
圖十五、肝癌病人對沙利竇邁治療之不良藥物反應 31
圖十六、性別對病人存活日數的影響 32
圖十七、年齡分組對病人存活日數的影響 33
圖十八、肝疾病組織病理對病人存活日數的影響 33
圖十九、肝疾病病因對病人存活日數的影響 34
圖二十、肝癌Okuda分期對病人存活日數的影響 34
圖二十一、Child-Turcotte-Pugh 計分對病人存活日數的影響 35
圖二十二、沙利竇邁治療前接受至少一次TACE治療對病人存活日數的影響 36
圖二十三、沙利竇邁治療反應情形對病人存活日數的影響 36
圖二十四、沙利竇邁可能的作用機轉 39
圖二十五、沙利竇邁免疫調節反應和抑制血管新生的作用機轉 41
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