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研究生:洪佳華
研究生(外文):Chia-Hua Hung
論文名稱:砷化合物治療肝細胞癌之藥動學與藥效學研究
論文名稱(外文):Pharmacokinetics and Pharmacodynamics of Arsenic Species in the Treatment of Hepatocellular Carcinomas
指導教授:楊志新楊志新引用關係
指導教授(外文):Chih-Shin Yang
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:臨床藥學研究所
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:2004
畢業學年度:92
語文別:中文
論文頁數:76
中文關鍵詞:肝細胞癌藥物動力學砷化合物
外文關鍵詞:Hepatocellular carcinomaspharmacokineticsarsenic species
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肝細胞癌是常見的固態腫瘤,在臺灣更高居惡性腫瘤死因之首,其治療方式目前仍以手術為主。然而,肝細胞癌在發現之初腫瘤常已進展,甚至侵犯到其它的組織器官,使得手術切除不可行,只能接受緩和性的治療方式,其中包括化學治療;但截至目前為止,對於肝細胞癌全身性化療藥物的選擇,仍無定論,也因此新藥開發及許多試驗仍持續進行中。近年來,三氧化二砷在急性前骨髓性白血病的治療上發現驚人的療效,且砷在癌症的治療於中國傳統醫學中長久以來都占有一席之地,所以砷化合物被廣泛研究於其它癌症上的可行性。
在本研究中,我們收集以三氧化二砷作為治療的晚期肝癌病人,利用液相層析法來分析血液及尿液中的砷化合物濃度,得到藥動參數,另外也使用多種肝功能測試法,評估病人的肝功能,希望能藉此了解肝功能是否影響砷在體內之代謝。結果顯示,肝癌病人可能有潛在的肝功能異常,使得砷之清除率降低,砷化合物在體內逐漸累積。
在細胞實驗方面,我們利用肝癌細胞株進行多種藥物的細胞毒性分析,包括三氧化二砷之併用與甲基砷化合物。結果發現在3 μM的三氧化二砷濃度下,才可看見併用之加成作用,然而此濃度在臨床上不易維持,因此臨床意義不高;五價甲基砷化物的細胞毒性,在外加的麩胱甘肽(glutathione)作用下,呈現兩種相反的結果,但是否與三價的甲基砷化合物之生成有關,我們無法得知。據目前的了解,還原五價砷化合物的過程尚需其它酵素的參與,只觀察glutathione之作用,或許是不足的,有待更進一步深入之研究。
Hepatocellular carcinoma is a common solid tumor worldwide and is the first cause of death of malignancy in Taiwan. Surgery is the main modality of treatment. However, hepatocellular carcinomas often progress at the initial presentation and even invade other tissues or organs, which made curative resection impossible and patients could only receive palliative therapy including chemotherapy. Until now, there has been no consensus on the systemic chemotherapy agents for hepatocellular carcinoma. Therefore, investigations of new drugs and clinical trials keep on going. Arsenic trioxide was used in the treatment of acute promyelocytic leukemia recently and remarkable efficacy was noted. Furthermore, arsenic plays an important role in the treatment of cancer in the traditional Chinese Medicine. Arsenic species were then widely tested for the possibility in other malignancy.
In our study, we recruited patients with advanced hepatocellular carcinoma using arsenic trioxide as their treatment. By means of liquid chromatography, we analyzed their blood and urine samples. Concentrations of arsenic species were obtained and pharmacokinetic parameters were calculated. Besides, we also conducted a variety of liver function tests to evaluate patients’ residual hepatic function. We hope to understand the effect of hepatic function on the elimination of arsenic species in the body. The results indicate patients with hepatocellular carcinoma may have potential hepatic impairment. As the result, the clearance of arsenic species decreases and gradually accumulates.
In the other portion of our study, various drugs were experimented in hepatocellular carcinoma cell lines for the assays of cytotoxicity, including combination therapies of arsenic trioxide and methylated arsenic species. The results show combination therapies exhibit an additive or synergistic effect only when the concentration of arsenic trioxide achieved 3 μM. However, it was hard to maintain this level in human body, so this result in the clinical practice may be valueless.
Cytotoxicities of pentavalent methylated arsenic species revealed diverse effects under the exogenous glutathione, and we could not conclude if these are associated with the production of trivalent methylated arsenic species. According to the previous research, enzymatic process other than glutathione may be involved in the reduction of pentavalent arsenic species, and glutathione only may be insufficient to reduce arsenic. We need further studies to confirm this idea.
第一章 緒論(Introduction) 1
第一節 前言 1
第二節 肝細胞癌(Hepatocellular carcinomas, HCC) 3
第三節 砷化合物(Arsenic species) 9
第二章 研究方法(Materials and Methods) 17
第一節 實驗材料及儀器 17
第二節 人體藥物動力學試驗 19
第三節 體外(in vitro)藥效學實驗 27
第三章 研究結果(Results) 31
第一節 人體藥物動力學試驗 31
第二節 體外藥效學實驗 47
第四章 討論(Discussion) 60
第一節 人體藥物動力學試驗 60
第二節 體外藥效學實驗 66
第五章 結論(Conclusion) 72
參考文獻(References) 73
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