Chan Ching-Man Loren. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 126-144). / Abstracts in English and Chinese. / Acknowledgement --- p.ii / Abstract --- p.iii / Table of Content --- p.vii / List of Figure --- p.ix / List of Abbreviations --- p.xii / Chapter Chapter One --- General Introduction / Chapter 1.1 --- Doxorubicin --- p.1 / Chapter 1.2 --- Antioxidants --- p.11 / Chapter 1.3 --- Flavonoids --- p.17 / Chapter 1.4 --- Protection against doxorubicin-induced cardiotoxicity by antioxidant --- p.25 / Chapter 1.5 --- Aim of research --- p.25 / Chapter Chapter Two --- Study of Cardioprotection Effect of Flavonoids Against Doxorubicin-induced Toxicity in Sprague-Dawley Rats / Chapter 2.1 --- Introduction --- p.27 / Chapter 2.2 --- Materials and Methods --- p.29 / Chapter 2.3 --- Results --- p.37 / Chapter 2.4 --- Discussion --- p.51 / Chapter ChapterThree --- Study of Effect of Flavonoids in Chemotherapy of Doxorubicinin Tumor-bearing Mice / Chapter 3.1 --- Introduction --- p.54 / Chapter 3.2 --- Materials and Methods --- p.56 / Chapter 3.3 --- Results --- p.63 / Chapter 3.4 --- Discussion --- p.80 / Chapter ChapterFour --- Study of the Effect of Flavonoids on Doxorubicin-induced Cytotoxicity on Human Tumor Cell Line and Doxorubicin-resistant Human Tumor Cell Line / Chapter 4.1 --- Introduction --- p.83 / Chapter 4.2 --- Materials and Methods --- p.86 / Chapter 4.3 --- Results --- p.94 / Chapter 4.4 --- Discussion --- p.120 / Chapter Chapter five --- Conclusion --- p.122 / References --- p.126

by Chan Hung Chuen. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 143-151). / Abstract also in Chinese. / Acknowledgments --- p.i / Abstract --- p.ii / Abstract (Chinese version) --- p.v / Abbreviations --- p.viii / Content --- p.ix / Chapter CHAPTER ONE --- INTRODUCTION / Chapter 1. --- Free radical and free radical-mediated antitumor drugs --- p.1 / Chapter 2. --- Mitomycin C (MC) / Chapter 2.1 --- Drug actions of MC --- p.2 / Chapter 2.2 --- Adverse side effects of MC --- p.5 / Chapter 3. --- Doxorubicin (DOX) / Chapter 3.1 --- Drug actions of DOX --- p.7 / Chapter 3.2 --- Adverse side effects of DOX --- p.8 / Chapter 4. --- Antioxidants --- p.14 / Chapter 5. --- Effects of exogenous ATP on the antitumor activity of Doxorubicin and Mitomycin C / Chapter 5.1 --- Glutathione (GSH) and related enzymes --- p.17 / Chapter 5.2 --- Glutathione (GSH) and Anticancer Quinones --- p.19 / Chapter 5.3 --- Glutathione and the cardiac toxicity of the anticancer drugs --- p.20 / Chapter 5.4 --- Glutathione depletion in tumor cells by exogenous ATP --- p.21 / Chapter 6. --- Aim of research --- p.24 / Chapter CHAPTER TWO --- THE EFFECT OF ANTIOXIDANTS ON DOXORUBICIN- OR MITOMYCIN C-INDUCED CYTOTOXICITY ON HUMAN TUMOR AND NORMAL CELL LINES / Chapter 2.1 --- Introduction --- p.26 / Chapter 2.2 --- Materials and Methods --- p.28 / Chapter 2.3 --- Results --- p.36 / Chapter 2.4 --- Discussion --- p.60 / Chapter CHAPTER THREE --- STUDY OF CARDIOPROTECTIVE EFFECTS OF ANTIOXIDANTS AGAINST DOXORUBICIN- OR MITOMYCIN C-INDUCED TOXICITY BY LANGENDORFF PERFUEED ISOLATED RAT HEART MODEL / Chapter 3.1 --- Introduction --- p.64 / Chapter 3.2 --- Materials and Methods --- p.67 / Chapter 3.3 --- Results --- p.75 / Chapter 3.4 --- Discussion --- p.76 / Chapter CHAPTER FOUR --- THE EFFECT OF ANTIOXIDANTS DURING CHEMOTHERAPY OF DOXORUBICIN OR MITOMYCIN C IN TUMOR-BEARING MICE / Chapter 4.1 --- Introduction --- p.78 / Chapter 4.2 --- Materials and Methods --- p.80 / Chapter 4.3 --- Results --- p.83 / Chapter 4.4 --- Discussion --- p.93 / Chapter CHAPTER FIVE --- HISTOLOGICAL STUDY AND LIPID PEROXIDATION STUDY OF PROTECTIVE EFFECT OF ANTIOXIDANTS IN TUMOR-BEARING MICE TREATED WITH DOXORUBICIN OR MITOMYCIN C / Chapter 5.1 --- Introduction --- p.95 / Chapter 5.2 --- Materials and Methods --- p.98 / Chapter 5.3 --- Results --- p.103 / Chapter 5.4 --- Discussion --- p.117 / Chapter CHAPTER SIX --- EFFECT OF EXOGENOUS ATP ON THE ANTITUMOR ACTIVITY OF DOXORUBICIN AND MITOMYCIN C ON CULTURED HUMAN HEPATOMA CELLS / Chapter 6.1 --- Introduction --- p.122 / Chapter 6.2 --- Materials and Methods --- p.124 / Chapter 6.3 --- Results --- p.126 / Chapter 6.4 --- Discussion --- p.136 / Chapter CHAPTER SEVEN --- CONCLUSION / Chapter 7.1 --- Conclusion --- p.139 / Chapter 7.2 --- Future perspective --- p.141 / Bibliography --- p.142

Hu Ying. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 95-122). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract (in English) --- p.ii / Abstract (in Chinese) --- p.iv / Table of contents --- p.vi / List of figures --- p.x / List of tables --- p.xi / Abbreviations --- p.vii / Chapter CHAPTER ONE: --- INTRODUCATION --- p.1 / Chapter 1.1 --- Hepatocellular Carcinoma --- p.2 / Chapter 1.1.1. --- Epidemiology of HCC --- p.2 / Chapter 1.1.2. --- The major risk factors --- p.2 / Chapter 1.1.3. --- Management of HCC --- p.3 / Chapter 1.2 --- Mechanisms of multidrug resistance (MDR) in cancer cells --- p.4 / Chapter 1.2.1. --- Major mechanisms in reduced drug accumulation --- p.5 / Chapter 1.2.1.1. --- P-glycoprotein (P-gp) --- p.6 / Chapter 1.2.1.2. --- Multidrug Resistance-associated Protein (MRP) --- p.7 / Chapter 1.2.1.3. --- Other effluxes --- p.8 / Chapter 1.2.2. --- Inhibition of apoptotic signaling pathways --- p.11 / Chapter 1.2.2.1. --- TP53 and multidrug resistance --- p.11 / Chapter 1.2.2.2. --- Anti-oncogene PTEN and drug resistance --- p.13 / Chapter 1.2.2.3. --- Influence of BCL2 family on drug resistance --- p.14 / Chapter 1.3 --- The chemotherapeutic agent of doxorubicin --- p.15 / Chapter 1.4 --- Aims of study --- p.18 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.20 / Chapter 2.1 --- Cell culture --- p.21 / Chapter 2.1.1 --- Cell lines and cell culture --- p.21 / Chapter 2.1.2 --- Subculture --- p.23 / Chapter 2.1.3 --- Cryopreservation --- p.23 / Chapter 2.1.4 --- Recovery of cryopreserved culture --- p.24 / Chapter 2.1.5 --- Cell number counting --- p.24 / Chapter 2.2 --- MTT experiments --- p.26 / Chapter 2.2.1 --- Determination of cell seeding density --- p.26 / Chapter 2.2.2 --- Cytotoxic assay --- p.27 / Chapter 2.3 --- Spectral Karytyping (SKY) --- p.27 / Chapter 2.3.1 --- Pretreatment of chromosome slides for SKY --- p.28 / Chapter 2.3.2 --- Hybridization --- p.28 / Chapter 2.3.3 --- Detection --- p.29 / Chapter 2.4 --- Positional expression profiling --- p.30 / Chapter 2.4.1 --- RNA extraction --- p.32 / Chapter 2.4.2 --- Reverse transcription and cDNA labling --- p.34 / Chapter 2.4.3 --- Probe purification and hybridization --- p.34 / Chapter 2.4.4 --- Image acquisition and data analysis --- p.35 / Chapter 2. 5 --- Quantitative RT-PCR --- p.37 / Chapter 2.5.1 --- RNA extraction --- p.37 / Chapter 2.5.2 --- Primer design --- p.37 / Chapter 2.5.3 --- Reverse transcription --- p.37 / Chapter 2.5.4 --- Quantitative PCR --- p.39 / Chapter 2.6. --- Statistical analysis --- p.40 / Chapter CHAPTER 3 --- RESULTS --- p.43 / Introduction --- p.44 / Chapter 3.1 --- Doxorubicin resistance in HCC cell lines --- p.44 / Chapter 3.2 --- Candidate drug resistance genes --- p.56 / Chapter 3.3 --- The roles of chromosomal instability --- p.58 / Chapter 3.4 --- Candidate resistance genes identified in chromosome 10 --- p.69 / Chapter CHAPTER 4 --- DISCUSSION --- p.75 / Introduction --- p.76 / Chapter 4.1 --- In vitro cell models facilitate drug resistance investigations --- p.11 / Chapter 4.2 --- Aneuploidy and DX resistance --- p.78 / Chapter 4.3 --- The role of known resistance genes on chromosome 10 --- p.79 / Chapter 4.4 --- Identification of novel DX resistance genes on chromosome 10 --- p.80 / Chapter 4.5 --- Common drug resistance genes --- p.83 / Chapter 4.5.1. --- The roles of classical drug resistance --- p.85 / Chapter 4.5.2. --- Inhibition of apoptosis and deregulation of cell cycle --- p.86 / Chapter CHAPTER 5 --- PROPOSED FUTURE STUDIES --- p.90 / Chapter 5.1. --- Validate significant in vitro findings by clinical trials --- p.91 / Chapter 5.2. --- Molecular mechanisms in inactivation of ECHS1 in resistant cells --- p.92 / Chapter 5.3. --- Future utilization of cDNA microarray data --- p.93 / REFERENCES --- p.95 / PUBLICATION --- p.122

Chau, Kin Fan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 106-119). / Abstract also in Chinese. / Abstract --- p.II / 摘要 --- p.VI / Acknowledgements --- p.IX / List of figures --- p.X / List of Abbreviations --- p.XII / Table of Contents --- p.XV / Chapter Chapter 1: --- Introduction / Chapter 1.1 --- Incidence and etiology of hepatocellular carcinoma (HCC) --- p.1 / Chapter 1.2 --- Structure of Hepatitis B Virus (HBV) --- p.2 / Chapter 1.3 --- Hepatitis B X protein (HBx) and HCC --- p.5 / Chapter 1.4 --- HBx and Apoptosis --- p.8 / Chapter 1.5 --- The role of Bcl-2 family in apoptosis and cell survival --- p.10 / Chapter 1.6 --- "Bid, the BH3-domain only protein" --- p.14 / Chapter 1.7 --- Dual Functions of Bid --- p.16 / Chapter 1.8 --- The relationship between Bid and HBx --- p.19 / Chapter 1.9 --- Hypoxia and HCC --- p.21 / Chapter 1.10 --- Hypoxia and HBx --- p.25 / Chapter 1.11 --- Hypoxia and Bid --- p.28 / Chapter 1.12 --- Aim of study --- p.29 / Chapter Chapter 2: --- Methods and materials / Chapter 2.1 --- Confirmation of the culture of the stable cell lines --- p.30 / Chapter 2.2 --- Doxorubicin treatment to the cell lines --- p.34 / Chapter 2.3 --- Culture of the cell lines under hypoxic conditions --- p.35 / Chapter 2.4 --- Protein sample preparations --- p.37 / Chapter 2.5 --- Determination of protein samples --- p.38 / Chapter 2.6 --- Sodium dodecyl sulfate 226}0ؤ polyacrylamide gel electrophoresis (SDS- PAGE) --- p.39 / Chapter 2.7 --- Transfer of protein to nitrocellulose membranes --- p.39 / Chapter 2.8 --- Western blot analysis of proteins --- p.41 / Chapter 2.8.1. --- Antibodies --- p.41 / Chapter 2.8.2. --- Determination of expression profiles of desired proteins by immunoblotting --- p.45 / Chapter 2.9 --- "Measurement of cell viability by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay" --- p.46 / Chapter 2.10 --- Determination of cell proliferation by BrdU proliferation assay --- p.47 / Chapter 2.11 --- Detection of apoptosis of the cell lines by TUNEL (Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling) --- p.50 / Chapter 2.12 --- Determination of the involvement of p38 MAPK in the generation of truncated Bid by p38 MAPK inhibitor SB203580 --- p.52 / Chapter Chapter 3: --- Results / Chapter 3.1 --- Confirmation of plasmids and the stable cell lines --- p.53 / Chapter 3.2 --- Morphology and the basic parameters of the cells with full-length HBx or mutant HBx --- p.53 / Chapter 3.3 --- Cell viability under doxorubicin treatment with or without hypoxia --- p.59 / Chapter 3.4 --- Determination of cell proliferation under stress --- p.70 / Chapter 3.5 --- Expression profiles of various proteins in the stable cell lines under doxorubicin treatment with or without hypoxia --- p.74 / Chapter 3.5.1. --- Verification of hypoxia --- p.74 / Chapter 3.5.2. --- Pro-apoptotic proteins --- p.74 / Chapter 3.5.3. --- Anti-apoptotic proteins --- p.74 / Chapter 3.6 --- Determination of apoptosis of various cell lines under stress --- p.82 / Chapter 3.7 --- "p38 MAPK, but not Akt, was activated by doxorubicin" --- p.87 / Chapter 3.8 --- The p38 MAPK inhibitor SB203580 could attenuate the cleavage of Bid --- p.89 / Chapter Chapter 4: --- Discussion --- p.92 / Chapter Chapter 5: --- Conclusion and future prospective --- p.103 / Chapter Chapter 6: --- References --- p.106

Chemotherapy persists as one of the mainstays of breast cancer treatment, particularly for triple-negative breast cancer which currently has no targeted treatment methods. While chemotherapy is beneficial for killing the malignant tumor cells, it leads to the release of damage-associated molecular patterns into the tumor microenvironment. Damage-associated molecular patterns are a contributing factor to cancer-related inflammation which can potentiate metastatic spread through several mechanisms such as the development of tumor microenvironments at metastastic sites. These damage-associated molecular patterns include nucleic acids, nucleic acid-associated lipids and vesicles, cytokines, and proteins such as high mobility group protein B1. Polyamidoamine (PAMAM) is a biodegradable, water-soluble dendrimer polymer with the ability to possess different charges and sizes depending on its terminal branches and degree of branching (i.e. generation number), respectively. Amine-terminated PAMAM-NH2 is positively charged and can bind to circulating DNA and RNA. Since most DAMP molecules are negatively charged, I hypothesized that a polycation such as PAMAM-NH2 would be an efficient nanomaterial to remove pathogenic NA DAMPs generated by chemotherapy. Building on this dendrimer, we synthesized modified cationic PAMAM-generation 3 derivatives with an aim to balance toxicity with NA-binding affinity and capacity to encapsulate chemodrugs. Our results found that these soluble and nanoparticle PAMAM materials can bind to both cell-free DNA and RNA released as a result of treating triple-negative breast cancer cells with chemotherapy drugs such as doxorubicin and paclitaxel. These PAMAM-G3 materials are termed as nucleic acid binding polymers and nucleic-acid binding polymeric nanoparticles.My thesis dissertation explores the anti-metastatic effects of nucleic-acid binding polymeric nanoparticles delivering the chemotherapy drug paclitaxel using in-vitro and in-vivo models. Two murine metastatic breast cancer models served as the basis for assessing the effects of conventional paclitaxel delivery compared to paclitaxel delivery from within PAMAM nucleic-acid binding polymeric nanoparticles with respect to primary tumor growth, extent of lung metastasis, and the systemic inflammatory response reflected in murine serum. Compared to treatment with unencapsulated paclitaxel, delivery of paclitaxel within the PAMAM nucleic-acid binding polymeric nanoparticles resulted in significantly decreased serum cell-free DNA levels, decreased inflammatory cytokines, and a lower degree of lung metastasis in the mice. The decrease in the degree of lung metastasis in mice receiving paclitaxel within the PAMAM nanoparticles was confirmed by assessing the photon flux signal of 4T1-luciferase breast cancer cells invading the murine lungs in both in-vivo and ex-vivo imaging and by using a machine learning method to quantify the degree of metastasis in H&E- stained sections of the lungs. The ability to mitigate the phenomenon of chemotherapy-induced cancer metastasis while effectively delivering the chemotherapy to the tumor microenvironment could help improve the outcomes of patients being treated with chemotherapy. This work developed a therapeutic cationic PAMAM nanocarrier-based strategy to inhibit paclitaxel-induced metastasis by scavenging cell-free nucleic acids and mitigating cell-free nucleic acid-induced inflammation.