ABSTRACT
Background: Diabetes mellitus is a metabolic disease characterized by hyperglycemia, which affects different tissues including the liver. Epidermal growth factor receptor [EGFR] family is one of the tyrosine kinase receptor families that regulate liver pathophysiology
Aim of the work: This study aimed to demonstrate the histological and EGFR immunohistochemical changes that occur in the liver of streptozotocin [STZ]-induced diabetic rat
Materials and methods: Twenty male albino rats divided into two groups, group I [control] and group II [diabetic], were used. Diabetes was induced in the animals in group II by a single intraperitoneal injection of STZ [40 mg/kg]. Five rats from each group were sacrificed 2 and 4 weeks after the STZ injection. Blood samples were collected for detection of serum glucose and insulin levels. Paraffin sections of the liver were prepared and stained with H and E, periodic acid Schiff, Masson's trichrome stains, and immunohistochemical stain using anti-EGFR antibody
Results: Diabetes mellitus was associated with marked congestion of central veins, blood sinusoids, and hepatic veins. Hepatocytes showed degenerative and fatty changes, especially in the periportal regions. Four weeks after induction of diabetes, signs of hepatic regeneration such as large binucleated hepatocytes were observed in the pericentral regions. Control livers showed strong positive EGFR immunoreactivity in hepatocytes, mainly in the periportal and pericentral regions, and in the bile duct epithelium. A marked decrease in EGFR immunoreactivity was observed in the livers of diabetic rats
Conclusion: Diabetes mellitus is associated with marked hepatic congestion, degenerative and fatty changes in the hepatocytes, and decreased hepatic EGFR immunoreactivity
Subject(s)
Animals, Laboratory , ErbB Receptors/immunology , Liver/pathology , RatsABSTRACT
To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.
Subject(s)
Animals , Humans , Antibodies, Monoclonal/pharmacology , Antigens, CD20/immunology , Drug Discovery , Immune System Diseases/drug therapy , Immunotherapy/trends , Molecular Targeted Therapy , Neoplasms/drug therapy , ErbB Receptors/immunology , Receptor, ErbB-2/immunology , Tumor Necrosis Factor-alpha/immunology , United States , United States Food and Drug Administration , Vascular Endothelial Growth Factor A/immunologyABSTRACT
To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.
Subject(s)
Animals , Humans , Antibodies, Monoclonal/pharmacology , Antigens, CD20/immunology , Drug Discovery , Immune System Diseases/drug therapy , Immunotherapy/trends , Molecular Targeted Therapy , Neoplasms/drug therapy , ErbB Receptors/immunology , Receptor, ErbB-2/immunology , Tumor Necrosis Factor-alpha/immunology , United States , United States Food and Drug Administration , Vascular Endothelial Growth Factor A/immunologyABSTRACT
Apoptosis seems to play an important role in cancer immunotherapy outcome. We have studied the kinetic pattern of apoptosis induction in H125 human lung carcinoma xenografts after treatment with the monoclonal antibody (MAb) anti-epidermal growth factor receptor (EGFr) IOR EGF/r3. Tumor-bearing nude mice were injected intravenously with a single 8 mg/kg dose of IOR EGF/r3 and tumor specimens were taken up to 30 days post treatment. Apoptosis was measured by morphometric analysis of the histological sections at each tumor specimen over time points. The results showed a significant apoptotic response in tumors within six days after injection of this MAb reaching a peak at 20 days post treatment. The kinetics were very broad, with apoptotic cells present over the entire time-frame. However, the time course of the apoptotic index showed a significant difference to the mitotic index. Finally, the MAb-induced apoptosis was related to tumor growth delay indicating a probable arrest of cell cycle and a corresponding inhibition of tumor progression, which was corroborated by the Ki67 and proliferating cell nuclear antigen (PCNA) biomarkers.
Subject(s)
Animals , Humans , Male , Mice , Antibodies, Monoclonal/pharmacology , Apoptosis/drug effects , Neoplasms/pathology , ErbB Receptors/immunology , Mice, NudeABSTRACT
Dysregulation of oncogenes, overproduction of growth factor receptors and their ligands, and loss of function of tumor suppressor genes are thought to contribute to multi-step process of carcinogenesis. It is suggested that proliferation markers like epidermal growth factor receptor (EGFR) actively participate in oral carcinogenesis, during initiation or promotion stage of the process. Potent mitogens such as epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-a) mediate their growth responses through the common transmembrane glycoprotein receptor, EGFR. Current data suggest that a good number of epithelial cancers including oral squamous cell carcinomas (OSCC) overexpress EGFR and that monoclonal antibodies directed against EGFR may provide valuable information that would be useful in planning proper palliative treatment of certain premalignant and malignant lesions derived from squamous epithelium.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Carcinoma, Squamous Cell/genetics , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/physiology , Humans , Immunohistochemistry , Mouth Neoplasms/genetics , ErbB Receptors/immunologyABSTRACT
Se determinó la expresión inmunohistoquímica del receptor del factor de crecimiento epidérmico en 24 carcinomas epidermoides infiltrantes de cuello uterino, 81 lesiones precursores, 47 de bajo y 34 de alto grado, 20 epitelios epidermoides normales, 11 epitelios epidermoides metaplásicos y 14 adenocarcinomas. Además, en 30 casos de estas lesiones se determinó mediante hibridación in situ la infección por tipos de VPH 6/11, 16/18 y 31/33/35. Se encontró mayor expresión de RFCE en lesiones de alto grado 64,7 por ciento, particularmente displasia moderada 72,2 por ciento, que en los epitelios controles 19,1 por ciento, lesiones de bajo grado 44,7 por ciento y carcinoma infiltrante 45,8 por ciento, con diferencias estadísticamente significativas sólo con los controles p<0,02. No se encontraron diferencias en la expresión de RFCE entre carcinoma epidermoide y nada, al menos inicialmente, al desarrollo del carcinoma de cuello uterino. por otro lado, el mayor porcentaje de infección de VPH tipos 16/18 que los otros tipos virales, en lesiones con expresión de RFCE, sugiere alguna asociación entre ambos factores