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This dissertation, Treatment of Hepatocellular Carcinoma With a Novel Gold Compound by Ching-tung, Lum, 林菁潼, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Treatment of hepatocellular carcinoma with a novel gold compound Submitted by Lum Ching Tung for the degree of Doctor of Philosophy at the University of Hong Kong in April, 2005 Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide among all malignancies and causes one million deaths annually. Most HCC patients are diagnosed at advanced stages and have unresectable tumors, and chemotherapy is the current therapy of choice for treating patients with unresectable tumors. Both anti-cancer drugs and gold compounds are used in treating rheumatoid arthritis, suggesting that they may have similar therapeutic effects in cancer. Recently, a series of gold(III) meso-tetraarylporphyrins which are stable against demetallation in physiological conditions have been synthesized. In this study, the anti-tumor effects of one of these compounds, gold(III) meso-tetraarylporphyrin 1a (gold-1a) was investigated using an orthotopic rat HCC model as well as two HCC cell lines. Gold-1a prolonged the survival of HCC rats and specifically induced necrosis as well as apoptosis in the tumor tissues of the rats but not in normal liver tissues. Noteworthy was the fact that gold-1a treatment did not cause significant drop of body weight of the rats. Moreover, both plasma ALT and AST levels decreased in response to gold-1a treatment, instigating that gold-1a might improve the liver functions of the rats. Gold-1a treatment inhibited the proliferation of a rat hepatoma cell line McA-RH7777. This growth inhibition was at least in part attributable to apoptosis induction by gold-1a. IC of gold-1a in McA-RH7777 and a rat normal liver cell line Clone 9 were 1.60.09 50 M and 5.30.11 M respectively, indicating that gold-1a was more toxic to cancer cells than to normal cells. Microarray studies demonstrated that gold-1a up-regulated three members of the growth arrest and DNA damage inducible (Gadd) gene family, which play important roles in growth inhibition and apoptosis, in McA-RH7777. Suppression of Gadd34 and Gadd153 in McA-RH7777 cells by small hairpin RNA (shRNA) reduced the gold-1a induced apoptosis and growth inhibition, further indicating that gold-1a mediated its actions at least in part via up-regulation of Gadd34 and Gadd153. In addition, gold-1a induced cleavage of caspase-3 and caspase-6 in McA-RH7777. Gold-1a was also demonstrated to induce G2/M cell cycle arrest in HepG2 human HCC cells, and Gadd45α mRNA was increased in these cells in response to gold-1a. However, whether Gadd45α is involved in the signal transduction of gold-1a induced cell cycle arrest, or it reflects only the growth arrest induced by the compound remains unclear. Moreover, gold-1a significantly inhibited tube formation in mouse endothelial cells and down-regulated the expression of an angiogenic factor, plasminogen activator inhibitor-1 (PAI-1), in McA-RH7777 cells. Collectively, gold-1a may be a promising agent for treating HCC patients. DOI: 10.5353/th_b3069992 Subjects: Liver - Cancer - ChemotherapyAntineoplastic agents - Physiological effectGold compounds - Therapeutic use

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