Pharmacokinetics and Pharmacodynamics of Arsenic Species in the Treatment of Hepatocellular Carcinomas

• Main Authors: Chia-Hua Hung, 洪佳華
• Other Authors: Chih-Shin Yang
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/23799049080818324253

碩士 === 國立臺灣大學 === 臨床藥學研究所 === 92 === 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.