by Chiu-lun Fok. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1991. / Includes bibliographical references. / List of Abbreviations --- p.i / Abstract --- p.iii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General Properties of Oxalysine --- p.1 / Chapter 1.1.1 --- Chemical Structure and Properties --- p.1 / Chapter 1.1.2 --- Biological Properties --- p.2 / Chapter 1.1.2.1 --- Antimicrobial Activity --- p.2 / Chapter 1.1.2.2 --- Antitumor Activity --- p.2 / Chapter 1.1.2.3 --- Immunomodulatory Activity --- p.5 / Chapter 1.1.2.4 --- Other Biological Properties --- p.5 / Chapter 1.1.3 --- Pharmacokinetics and Toxicity --- p.6 / Chapter 1.2 --- General Properties of Ribosome-Inactivating and Abortifacient Proteins --- p.8 / Chapter 1.2.1 --- Research History --- p.8 / Chapter 1.2.1.1 --- Ribosome-Inactivating Proteins --- p.8 / Chapter 1.2.1.2 --- Abortifacient Proteins --- p.9 / Chapter 1.2.2 --- Relationship between Ribosome- Inactivating Proteins and Abortifacient Proteins --- p.10 / Chapter 1.2.3 --- Distribution --- p.11 / Chapter 1.2.4 --- Physicochemical Characteristics --- p.12 / Chapter 1.2.5 --- Biological Properties --- p.13 / Chapter 1.2.5.1 --- Effect on Protein Synthesis --- p.13 / Chapter 1.2.5.2 --- Effect on the Immune System --- p.14 / Chapter 1.2.5.3 --- Cytotoxic and Antitumor Activities --- p.16 / Chapter 1.2.5.4 --- Termination of Pregnancy --- p.17 / Chapter 1.2.5.5 --- Antiviral Activity --- p.18 / Chapter 1.2.6 --- The Study on Luffaculin --- p.19 / Chapter 1.3 --- Aim of the Present Study --- p.20 / Chapter 1.3.1 --- Oxalysine --- p.20 / Chapter 1.3.2 --- Luffaculin --- p.20 / Chapter Chapter 2 --- Materials and Methods --- p.22 / Chapter 2.1 --- Materials --- p.22 / Chapter 2.2 --- Methods --- p.30 / Chapter 2.2.1 --- In Vivo Drug Treatment --- p.30 / Chapter 2.2.2 --- Isolation and Preparation of Cells --- p.30 / Chapter 2.2.2.1 --- Peritoneal Exudate Cells --- p.30 / Chapter 2.2.2.2 --- Spleen Cells --- p.30 / Chapter 2.2.2.3 --- Ficoll-Paque Separation of Lymphocytes --- p.31 / Chapter 2.2.2.4 --- Congo Red-Stained Yeast Cells --- p.31 / Chapter 2.2.3 --- Lymphocyte Transformation --- p.32 / Chapter 2.2.4 --- Haemolytic Plaque Assay --- p.33 / Chapter 2.2.5 --- Phagocytic Activity --- p.33 / Chapter 2.2.6 --- Macrophage-Mediated Cytostatic Activity --- p.34 / Chapter 2.2.7 --- Delayed Type Hypersensitivity (DTH) --- p.35 / Chapter 2.2.8 --- Production of and Assay for Interleukin-2(IL-2) --- p.36 / Chapter 2.2.9 --- Cytotoxicity of the Drugs on Various Cell Lines --- p.38 / Chapter 2.2.9.1 --- Trypan Blue Exclusion Method --- p.38 / Chapter 2.2.9.2 --- Neutral Red Uptake Method --- p.38 / Chapter 2.2.10 --- Cytostatic Effect of the Drugs on Various Cell Lines --- p.39 / Chapter 2.2.11 --- Evaluation of Antitumor Activity (In Vivo ) --- p.40 / Chapter 2.2.11.1 --- Tumor Size --- p.40 / Chapter 2.2.11.2 --- Survival Study --- p.40 / Chapter 2.2.12 --- TLC Analysis --- p.40 / Chapter 2.2.13 --- Preparation of Ribosome-Inactivating and Abortifacient Proteins --- p.41 / Chapter 2.2.13.1 --- Trichosanthin (TCS) --- p.41 / Chapter 2.2.13.2 --- Luffaculin (LFC) --- p.42 / Chapter 2.2.14 --- Protein Determination --- p.42 / Chapter 2.2.15 --- Statistical Analysis --- p.43 / Chapter Chapter 3 --- The Immunomodulatory and Antitumor Activities of Oxalysine (OXL) --- p.44 / Chapter 3.1 --- Introduction --- p.44 / Chapter 3.2 --- The Immunomodulatory Activity of Oxalysine --- p.46 / Results --- p.46 / Chapter 3.2.1 --- Effect of Oxalysine on the Proliferation of Mouse Splenocytes --- p.46 / Chapter 3.2.2 --- Effect of In Vitro Oxalysine Exposure on the Response of Murine Splenocytes to Mitogens --- p.46 / Chapter 3.2.3 --- Effect of In Vivo Oxalysine Treatment on the Response of Murine Splenocytes to Mitogens --- p.49 / Chapter 3.2.4 --- Effect of Oxalysine on Delayed Type Hypersensitivity (DTH) Response --- p.51 / Chapter 3.2.5 --- Effect of Oxalysine on the In Vitro Phagocytic Activity of Mouse Peritoneal Macrophages --- p.51 / Chapter 3.2.6 --- Effect of Oxalysine on Macrophage- Mediated Cytostatic Activity --- p.53 / Chapter 3.2.7 --- Effect of Oxalysine on the Humoral Response to SRBC --- p.55 / Discussion --- p.59 / Chapter 3.3 --- Mechanistic Studies on Inhibition of Mitogen´ؤ Induced Lymphocyte Transformation by Oxalysine --- p.62 / Results --- p.62 / Chapter 3.3.1 --- Lack of Direct Cytotoxic Effect of Oxalysine on Mouse Splenocytes In Vitro --- p.62 / Chapter 3.3.2 --- Effect of Oxalysine on the Kinetics of Con A-Induced Lymphoproliferative Response --- p.62 / Chapter 3.3.3 --- Time Course Studies on the Effect of Oxalysine on Mitogen-Induced Lymphocyte Transformation --- p.64 / Chapter 3.3.3.1 --- Preincubation of Oxalysine --- p.64 / Chapter 3.3.3.2 --- Delayed Addition of Oxalysine --- p.67 / Chapter 3.3.4 --- Effect of Exogenous IL-2 on the Oxalysine-Mediated Suppression of Lymphocyte Blastogenesis --- p.69 / Chapter 3.3.5 --- Effect of Oxalysine on the Activity of IL-2 Containing Medium to Maintain the Proliferation of the IL´ؤ2 Dependent CTLL-2 Cells --- p.73 / Chapter 3.3.6 --- Production of IL-2 from Splenocytes of Oxalysine´ؤTreated Mice --- p.75 / Chapter 3.3.7 --- The In Vitro Effect of Oxalysine on the Production of IL-2 from Con A-Activated Mouse Splenocytes --- p.75 / Discussion --- p.79 / Chapter 3.4 --- The Antitumor Activity of Oxalysine --- p.83 / Results --- p.83 / Chapter 3.4.1 --- Cytotoxicity of Oxalysine on Various Tumor Cell Lines --- p.83 / Chapter 3.4.2 --- Cytostatic Effect of Oxalysine on Various Tumor Cell Lines --- p.85 / Chapter 3.4.3 --- Effect of Oxalysine on the Survival of Tumor-Bearing Mice --- p.93 / Chapter 3.4.4 --- Effect of Oxalysine on the Growth of Transplantable Tumor Cells In Vivo --- p.95 / Discussion --- p.100 / Chapter 3.5 --- General Discussion --- p.102 / Chapter Chapter 4 --- The Immunomodulatory and Cytotoxic Properties of Luffaculin (LFC) --- p.104 / Chapter 4.1 --- Introduction --- p.104 / Chapter 4.2 --- The Immunomodulatory Activity of Luffaculin --- p.106 / Results --- p.106 / Chapter 4.2.1 --- Lack of Direct Cytotoxic Effect of LFC on Mouse Splenocytes In Vitro --- p.106 / Chapter 4.2.2 --- Effect of Luffaculin on the Proliferation of Mouse Splenocytes --- p.108 / Chapter 4.2.3 --- Inhibition of the Mitogen-Induced Lymphocyte Transformation by Luffaculin --- p.108 / Chapter 4.2.4 --- Effect of Luffaculin on Delayed Type Hypersensitivity (DTH) Response --- p.114 / Chapter 4.2.5 --- Primary Humoral Immune Response to SRBC in Luffaculin-Treated Mice --- p.114 / Chapter 4.2.6 --- Effect of Luffaculin on Phagocytosis of Macrophages In Vitro --- p.117 / Chapter 4.2.7 --- Effect of Luffaculin on Macrophage- Mediated Cytostatic Activity --- p.117 / Chapter 4.2.8 --- Production of Interleukin´ؤ2 from Splenocytes of Luffaculin-Treated Mice --- p.119 / Discussion --- p.122 / Chapter 4.3 --- The Cytotoxic and Cytostatic Effects of Luffaculin on Various Tumor Cell Lines --- p.125 / Results --- p.125 / Chapter 4.3.1 --- Cytotoxicity of Luffaculin on Various Tumor Cell Lines --- p.125 / Chapter 4.3.2 --- Cytostatic Effect of Luffaculin on Various Tumor Cell Lines --- p.127 / Discussion --- p.138 / Chapter 4.4 --- General Discussion --- p.140 / References --- p.143

by Sze Shun Fai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1992. / Includes bibliographical references (leaves 132-139). / Abstract --- p.1 / Chapter Chapter 1 --- General Introduction / Chapter 1.1 --- The pineal gland --- p.5 / Chapter 1.2 --- Discovery of melatonin --- p.5 / Chapter 1.3 --- Synthesis of melatonin --- p.5 / Chapter 1.4 --- Physiology of melatonin and its derivatives --- p.6 / Chapter 1.5 --- In vitro tumor biology of melatonin and its derivatives --- p.7 / Chapter 1.6 --- In vivo tumor biology of melatonin --- p.10 / Chapter 1.7 --- Macrophages --- p.11 / Chapter 1.8 --- Lymphocytes --- p.14 / Chapter Chapter 2 --- Toxicity of pineal indoles on tumor cell lines / Chapter 2.1 --- General introduction --- p.17 / Chapter 2.2 --- Material and methods --- p.18 / Chapter 2.3 --- Results --- p.22 / Chapter 2.4 --- Discussion --- p.23 / Chapter Chapter 3 --- Activation of murine peritoneal macrophages by melatonin and methoxytryptamine / Chapter 3.1 --- General introduction --- p.37 / Chapter 3.2 --- Material and methods --- p.38 / Chapter 3.3 --- Results --- p.55 / Chapter 3.4 --- Discussion --- p.61 / Chapter Chapter 4 --- Activation of murine splenocytes by melatonin and methoxytryptamine / Chapter 4.1 --- General introduction --- p.81 / Chapter 4.2 --- Material and methods --- p.82 / Chapter 4.3 --- Results --- p.91 / Chapter 4.4 --- Discussion --- p.128 / Chapter Chapter 5 --- General discussion --- p.132 / References

by Chen Paul. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 141-150). / Chapter 1. --- INTRODUCTION --- p.1 / Chapter 1.1 --- Immunomodulation --- p.1 / Chapter 1.2 --- Effector cells mediating anti-tumour immunity --- p.1 / Chapter 1.2.1 --- Cytotoxic T Lymphocytes --- p.3 / Chapter 1.2.2 --- Macrophages --- p.4 / Chapter 1.2.3 --- Natural Killer Cells --- p.5 / Chapter 1.2.4 --- Lymphokine-activated Killer (LAK) --- p.6 / Chapter 1.3 --- Cytokines as immunomodulators in cancer therapy --- p.7 / Chapter 1.3.1 --- Tumour Necrosis Factor-α (TNF-α) --- p.7 / Chapter 1.3.2 --- Interleukin-1 (IL-1) --- p.9 / Chapter 1.3.3 --- Interleukin-2 (IL-2) --- p.9 / Chapter 1.3.4 --- Granulocytes/Macrophages Colony-Stimulating Factors --- p.10 / Chapter 1.4 --- Polysaccharides as potential immunostimulating agents --- p.11 / Chapter 1.5 --- General properties of Klebsiella pneumoniae --- p.12 / Chapter 2. --- AIM AND SCOPE OF THIS DISSERTATION --- p.16 / Chapter 3. --- MATERIALS AND METHODS --- p.18 / Chapter 3.1 --- Materials --- p.18 / Chapter 3.1.1 --- Animals --- p.18 / Chapter 3.1.2 --- Klebsiella pneumoniae K24 --- p.18 / Chapter 3.1.3 --- Cell lines --- p.18 / Chapter 3.1.4 --- "Buffer, Culture media and Chemicals" --- p.19 / Chapter 3.2 --- Methods --- p.27 / Chapter 3.2.1 --- Extraction and Characterization of Klebsiella pneumoniae K24 Capsular Polysaccharide (K24 CPS) --- p.27 / Chapter 3.2.2 --- Assays of Immunomodulatory Activities of K24 CPS on Lymphocytes --- p.30 / Chapter 3.2.3 --- Assays of Immunomodulatory Effect of K24 CPS on Macrophages --- p.34 / Chapter 3.2.4 --- Assays of Anti-Tumour Activities of K24 CPS --- p.39 / Chapter 3.2.5 --- Assays of the Effects of K24 CPS on the Proliferation and Differentiation of Murine Bone Marrow Cells --- p.54 / Chapter 3.2.6 --- Assays of the Immunorestorative Activities of K24 CPS --- p.56 / Chapter 4. --- EXTRACTION AND CHARACTERIZATION OF KLEBSIELLA PNEUMONIAE K24 CAPSULAR POLYSACCHARIDE (K24 CPS) --- p.59 / Chapter 4.1 --- Preparation of Klebsiella pneumoniae K24 CPS Capsular Polysaccharide (K24 CPS) --- p.59 / Chapter 4.2 --- Acetic Acid Treatment of K24 CPS --- p.59 / Chapter 4.3 --- Gel Filtration --- p.59 / Chapter 4.4 --- Carbohydrate and Protein contents of K24 CPS --- p.61 / Chapter 4.5 --- Cytotoxicity Assay using Artemia franciscana (Brine Shrimp) --- p.61 / Chapter 5. --- IMMUNOMODULATORY EFFECTS OF K24 CPS --- p.68 / Chapter 5.1 --- The Effect of K24 CPS in vitro Mitogenic Assay of K24 CPS using Murine Splenocytes --- p.68 / Chapter 5.2 --- The in vivo Mitogenic Effect of K24 CPS on Murine Splenic Lymphocytes --- p.73 / Chapter 5.3 --- The Effect of K24 CPS on the Production of Interleukin-2 (IL-2)-like substance by Murine Splenocytes --- p.73 / Chapter 5.4 --- The effect of K24 CPS on the in vitro Stimulation of Murine Macrophage Nitric Oxide (NO) Production --- p.73 / Chapter 5.5 --- The effect of K24 CPS on the in vitro Stimulation of Macrophage Interleukin-1-like Production --- p.77 / Chapter 5.6 --- The effect of K24 CPS on in vivo Migration of Macrophage --- p.82 / Chapter 5.7 --- The effect of K24 CPS in vitro Stimulation of Macrophage Tumour Necrosis Factor- a (TNF-a) Production --- p.82 / Chapter 6. --- IN VITRO ANTI-TUMOUR EFFECT OF K24 CPS --- p.89 / Chapter 6.1 --- The in vitro Cytostatic effect of K24 CPS on the Suppression of EAT growth --- p.89 / Chapter 6.2 --- The effect of K24 CPS on cell cycle of EAT cells --- p.89 / Chapter 6.3 --- Study of the cytostatic effect of K24 CPS on EAT cells using Western Analysis --- p.93 / Chapter 6.3.1 --- Pattern of Phosphotyrosine Proteins --- p.93 / Chapter 6.3.2 --- Pattern of Phosphoserine Proteins --- p.96 / Chapter 6.3.3 --- Pattern of Phosphothreonine Proteins --- p.96 / Chapter 6.3.4 --- Level of c-fos --- p.99 / Chapter 6.3.5 --- Level of c-jun --- p.99 / Chapter 6.3.6 --- Level of c-myc --- p.102 / Chapter 7. --- THE IN VIVO ANTI-TUMOUR ACTIVITIES OF K24 CPS --- p.103 / Chapter 7.1 --- The effect of K24 CPS on the In vivo Suppression of EAT growth --- p.103 / Chapter 7.2 --- The effect of K24 CPS on the survival of EAT-bearing mice --- p.103 / Chapter 7.3 --- The effect of K24 CPS on the in vivo induction of Natural Killer (NK) Cell Cytotoxicity --- p.111 / Chapter 7.4 --- The effect of K24 CPS in vitro induction of Lymphokine-activated Killer (LAK) Cell Cytotoxicity --- p.111 / Chapter 7.5 --- The effect of K24 CPS on the in vivo Induction of Lymphokine-activated Killer (LAK) Cell Cytotoxicity --- p.114 / Chapter 7.6 --- The effect of K24 CPS on the endogenous production of TNF-α --- p.114 / Chapter 7.7 --- The effect of K24 CPS on the endogenous TNF-α production and EAT growthin vivo --- p.117 / Chapter 8. --- THE IMMUNORESTORATIVE ACTIVITIES OF K24 CPS --- p.122 / Chapter 8.1 --- The in vivo Immunorestorative Activities of K24 CPS in EAT-bearing Mice --- p.122 / Chapter 8.2 --- The in vitro Immunorestorative Activities of K24 CPS in Mice bearing 10-day-old- EAT --- p.122 / Chapter 9. --- THE EFFECT OF K24 CPS IN VITRO INDUCTION OF MURINE BONE MARROW CELLS PROLIFERATION AND DIFFERENTIATION --- p.126 / Chapter 9.1 --- The effect of K24 CPS in vitro induction of Murine Bone Marrow Cells Proliferation --- p.126 / Chapter 9.2 --- The effect of K24 CPS in vitro induction of Murine Bone Marrow Cells Differentiation --- p.126 / Chapter 10. --- CONCLUSIONS AND FUTURE PERSPECTIVES --- p.135 / Chapter 11. --- BIBLIOGRAPHY --- p.141

Le mélanome est le cancer cutané le plus invasif. Au cours de l’invasion tumorale et de la dissémination métastatique, les cellules tumorales sont capables de dégrader la matrice extracellulaire par la sécrétion de protéases telles que les MMPs. Lors de cette protéolyse matricielle, différents fragments de la matrice extracellulaire exerçant des activités anti-tumorale et/ou anti-angiogénique, nommés matrikines, sont libérés et modulent la croissance tumorale. De nombreuses matrikines dérivées des collagènes de membrane basale sont capables de limiter la progression tumorale. Nous avons étudié les propriétés anti-tumorales du domaine NC1 α4(IV), nommé tétrastatine, à la fois in vitro et in vivo dans un modèle de mélanome humain. La tétrastatine induit une inhibition de la prolifération et de l’invasion des cellules de mélanome in vitro. L’inhibition de prolifération est corrélée à un retard en phase G1/S du cycle cellulaire en présence de tétrastatine. L’inhibtion de l’invasion peut notamment s’expliquer par une inhibition de l’activation de la MMP-14 et une modification de sa répartition cellulaire, avec perte du phénotype migratoire en présence de tétrastatine. In vivo, la surexpression de la tétrastatine induit une forte inhibition de la croissance tumorale, dans un modèle de xénogreffe de mélanome humain chez la souris nude. Nous avons également pu identifier l’intégrine αvβ3 comme un récepteur potentiel de la tétrastatine. Enfin, l’étude des capacités anti-prolifératives et anti-invasives des cellules UACC 903 en présence de différents peptides permet aujourd’hui de mieux préciser la séquence responsable de l’activité anti-tumorale de ce domaine. En conclusion, la tétrastatine est une nouvelle matrikine à fort potentiel anti-tumoral capable de limiter la progression du mélanome. / Melanoma is the most invasive cutaneous cancer. During tumor invasion and metastatic dissemination, tumor cells degrade the extracellular matrix by secretion of proteases such as MMPs. During matrix proteolysis, fragments of the extracellular matrix with anti-tumor and/or anti-angiogenic activities, called matrikines, are released and modulate tumor growth. Many matrikines derived from basement membrane collagens are able to inhibit tumor progression. We studied the anti-tumor properties of the domain NC1 α4 (IV), named tetrastatin, both in vitro and in vivo in a human melanoma model. Tetrastatin induces inhibition of proliferation and invasion of melanoma cells in vitro. This inhibition of proliferation is correlated to a cell cycle delay in G1/S phase when cells are incubated with tetrastatin. The inhibition of invasion could be due, at least partly, to the inhibition of MMP-14 active form and modification of its cellular distribution, with a loss of the migratory phenotype in the presence of tetrastatin. In vivo, tetrastatin overexpression induces a strong inhibition of tumor growth, in a human melanoma xenograft model in nude mice. We also identified integrin αvβ3 as a potential receptor of tetrastatin. Finally, the study of the anti-proliferative and anti-invasive properties of the UACC 903 cells in the presence of different peptides allows us to better identify the sequence responsible of the anti-tumor activity. In conclusion, tetrastatin is a new potent anti-tumor matrikine capable of limiting melanoma progression.

Thesis (Ph. D.)--University of Nevada, Reno, 2000. / Includes bibliographical references. Online version available on the World Wide Web.

Diss. (sammanfattning) Linköping : Univ., 2001. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 6 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2010. / Härtill 4 uppsatser.