ABSTRACT
INTRODUCTION: The insulin-like growth factor type 1 (IGF-1) receptor contributes importantly to transformation and survival of tumor cells both in vitro and in vivo, and selective antagonists of the IGF-1 receptor (IGF-1R) activity represent an attractive experimental approach for human cancer therapy. METHODS: Using a phage display library, we identified several high-affinity fully human monoclonal antibodies with inhibitory activity against both human and rodent IGF.1Rs. RESULTS: These candidate therapeutic antibodies recognized several distinct epitopes and effectively blocked ligand-mediated receptor signal transduction and cellular proliferation in vitro. They also induced IGF-1R downregulation and catabolism following antibody-mediated endocytosis. These antibodies exhibited activity against human, primate, and rodent IGF-1Rs, and dose-dependently inhibited the growth of established human tumors in nude mice. CONCLUSION: These fully human antibodies therefore have the potential to provide an effective anti-tumor biological therapy in the human clinical setting.
Subject(s)
Antibodies, Monoclonal/pharmacology , Cell Proliferation/drug effects , Receptor, IGF Type 1/immunology , 3T3 Cells , Animals , Antibody Affinity , Cell Line, Tumor , Dose-Response Relationship, Drug , Down-Regulation , Epitope Mapping , Humans , Mice , Mice, Nude , Receptor, IGF Type 1/metabolism , Signal Transduction/drug effects , Transfection , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , Tumor Cells, Cultured/pathologyABSTRACT
Manganese has wide industrial applications and exposure to manganese can result in serious health conditions. The purpose of this study was to determine the reproductive effect of oral manganese exposure in male mice. Manganese acetate was tested at three dose levels (7.5, 15.0, and 30.0 mg/kg/day) for 43 days. The control group (0 mg/kg/day) received distilled water. Control negative group did not receive anything. Reproductive organ weights were recorded. Histopathology was performed on right testis, epididymis, seminal vesicle, and the accessory glands. Cauda epididymal, testicular sperm counts, and sperm motility was evaluated on the organ from the left side. The results of this study suggest that exposure to manganese caused a statistically significant (P<0.001) decrease in sperm motility and sperm counts at 15.0 and 30.0 mg/kg/day. There were no alterations in the fertility or pathology of the testicular tissue in the manganese-treated mice when compared with the controls.
