Man, Chi Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 141-184). / Abstract also in Chinese. / Acknowledgements --- p.ii / Abstract --- p.iv / Abbreviations --- p.xi / List of Tables --- p.xviii / List of Figures --- p.xx / Major Conference Presentations --- p.xxii / Publications in Preparation --- p.xxiv / Study Flowchart --- p.xxv / Chapter Chapter 1 --- Study Background --- p.1 / Chapter 1. --- Introduction --- p.2 / Chapter 1.1. --- General Overview of Adolescent Idiopathic Scoliosis (AIS) --- p.2 / Chapter 1.2. --- Natural History --- p.3 / Chapter 1.3. --- Current Treatments --- p.5 / Chapter 1.4. --- Additional Phenotypes Abnormalities --- p.9 / Chapter 1.5. --- Bone Modeling and Remodeling in Adolescents --- p.14 / Chapter 1.6. --- Bone Development --- p.15 / Chapter 1.7. --- Bone (re)modeling by osteoclasts and osteoblasts --- p.17 / Chapter 1.8. --- Factors Affecting Osteoblasts Regulation --- p.19 / Chapter 1.9. --- Current Hypothesis on the Etiology of AIS --- p.21 / Chapter 1.10. --- Melatonin --- p.26 / Chapter Chapter 2 --- Hypothesis and Objectives --- p.47 / Chapter 2. --- Hypothesis and Objectives --- p.48 / Chapter 2.1. --- Study Hypothesis --- p.48 / Chapter 2.2. --- Objectives --- p.48 / Chapter Chapter 3 --- Study on the Anthropometric Parameters and Bone Geometry of Girls with Severe AIS --- p.49 / Chapter 3.1. --- Introduction --- p.50 / Chapter 3.2. --- Methodology --- p.51 / Chapter 3.2.1. --- Recruitment of Subjects --- p.51 / Chapter 3.2.2. --- Evaluation of Curve Severity of Scoliosis --- p.52 / Chapter 3.2.3. --- Anthropometric Measurements --- p.53 / Chapter 3.2.4. --- Measurements of BMD --- p.53 / Chapter 3.2.5. --- Data Analysis --- p.54 / Chapter 3.3. --- Results --- p.55 / Chapter 3.3.1. --- Anthropometry --- p.55 / Chapter 3.3.2. --- BMD of Femoral Neck and Midshaft of Radius --- p.56 / Chapter 3.4. --- Discussion --- p.57 / Chapter Chapter 4 --- Response of Osteoblasts to Melatonin in AIS Girls In vitro Study --- p.69 / Chapter 4.1. --- Introduction --- p.70 / Chapter 4.2. --- Methodology --- p.72 / Chapter 4.2.1. --- Subjects Recruitments --- p.72 / Chapter 4.2.2. --- Cell Isolation --- p.73 / Chapter 4.2.3. --- Effect of Melatonin on Proliferation and Differentiation of AIS Osteoblasts --- p.76 / Chapter 4.2.4. --- Data Analysis --- p.79 / Chapter 4.3. --- Results --- p.80 / Chapter 4.3.1. --- Isolated Osteoblasts from Normal Human and AIS Patients --- p.80 / Chapter 4.3.2. --- Effect of Melatonin on Osteoblasts Proliferation --- p.80 / Chapter 4.3.3. --- Effect of Melatonin on Cell Differentiation --- p.81 / Chapter 4.4. --- Discussion --- p.83 / Chapter Chapter 5 --- Expression of MT1 and MT2 receptors in AIS Osteoblasts --- p.101 / Chapter 5.1. --- Introduction --- p.102 / Chapter 5.2. --- Methodology --- p.104 / Chapter 5.2.1. --- Osteoblast Samples --- p.104 / Chapter 5.2.2. --- Protein Expression of Melatonin Receptors in AIS Osteoblasts. --- p.105 / Chapter 5.2.3. --- Genotyping of MT2 receptors by Restriction Fragment Length Polymorphism (RFLP) --- p.109 / Chapter 5.2.4. --- Clinical Evaluations of the AIS Patients --- p.110 / Chapter 5.2.5. --- Data Analysis --- p.110 / Chapter 5.3. --- Results --- p.111 / Chapter 5.3.1. --- Semi quantification of Melatonin Receptors in AIS Osteoblasts 111 --- p.111 / Chapter 5.3.2. --- RFLP --- p.112 / Chapter 5.3.3. --- Functional Response Between the Different AIS Groups --- p.112 / Chapter 5.3.4. --- Correlation of the Clinical Phenotypes with the Different AIS Subgroups --- p.114 / Chapter 5.4. --- Discussion --- p.115 / Chapter Chapter 6 --- Summary and Conclusion --- p.132 / Chapter 6.1. --- Summary and Discussion --- p.133 / Chapter 6.2. --- Limitations and Further Studies --- p.136 / Chapter 6.3. --- Conclusion --- p.138 / Bibliography --- p.141 / Appendix I --- p.185 / Appendix II --- p.186 / Appeddix III --- p.187 / Appendix IV --- p.188 / Appendix V --- p.189 / Appendix VI --- p.190

Graduation date: 1993

On the basis of clinical studies, some researchers have advocated that the neurohormone and antioxidant melatonin, shown to possess intrinsic anticancer properties, be used as co-therapy in cancer patients being treated with the antineoplastic agent 5-fluorouracil, as increased patient survival times and enhanced quality of life have been observed. The focus of this research was thus to investigate the mechanisms of this seemingly beneficial drug interaction between 5-fluorouracil and melatonin. Metabolism studies were undertaken, in which it was established that there is no hepatic metabolic drug interaction between these agents by cytochrome P450, and that neither agent alters the activity of this enzyme system. Co-therapy with melatonin is thus unlikely to alter plasma levels of 5-fluorouracil by this mechanism. Novel mechanisms by which 5-fluorouracil is toxic were elucidated, such as the induction of lipid peroxidation, due to the formation of reactive oxygen species; decreases in brain serotonin, dopamine and norepinephrine levels, possibly leading to depression; hippocampal shrinkage and morphological alterations and lysis of hippocampal cells, which may underlie cognitive impairment; and a reduction in the nociceptive threshold when administered acutely. All these deleterious effects are attenuated by the co-administration of melatonin, suggesting that the agent exhibits antidepressive and analgesic properties, in addition to its known antioxidative and free radical-scavenging abilities. This suggests that melatonin cotherapy can significantly decrease 5-fluorouracil-induced toxicity, but this may also exert a protective effect on cancer cells and thus compromise the anticancer efficacy of 5-fluorouracil. It was, furthermore, found that stimulation of indoleamine 2,3-dioxygenase activity, mediated by increases in superoxide anion and interferon-γ levels, may underlie resistance to 5-fluorouracil therapy. Melatonin was shown to increase superoxide anion levels in vivo, and this is believed to be by conversion to the metabolite and known oxidant 6- hydroxymelatonin. This highlights that the possible deleterious effects of melatonin metabolites should be studied further. Serum corticosterone levels and cytokine profiles are unaltered by both 5-FU and melatonin, suggesting that these agents may be used by HIV infected individuals without promoting the progression to AIDS. It can thus be concluded that melatonin co-therapy is potentially useful in countering 5-fluorouracil toxicity.