Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors.

摘要: The overexpression in tumor cells of (proto)-oncogenic receptor tyrosine kinases such as epidermal growth factor (EGFR) or ErbB2/neu (also known HER-2) is generally thought to contribute the development solid tumors primarily through their effects on promoting uncontrolled cell proliferation. However, agents that antagonize function protein products encoded by these (proto)-oncogenes are behave vivo a cytotoxic-like manner. This implies oncogenes may regulate critical survival functions, including angiogenesis. latter could occur consequence regulation relevant factors oncogenes. We therefore sought determine whether EGFR angiogenesis examining expression vascular endothelial (VEGF)/vascular permeability (VPF), one most important all inducers found vitro treatment EGFR-positive A431 human epidermoid carcinoma cells, which be heavily dependent VEGF/VPF an factor, with C225 anti-EGFR neutralizing antibody caused dose-dependent inhibition VEGF expression. Prominent suppression vivo, well significant reduction blood vessel counts, were also observed established shortly after injection few four times into nude mice. Transformation NIH 3T3 fibroblasts mutant ErbB2/neu, another EGFR-like oncogenic kinase, resulted induction VEGF/VPF, and magnitude this effect was further elevated hypoxia. Moreover, ErbB2/neu-positive SKBR-3 breast cancer specific anti-ErbB2/neu monoclonal (4D5) Taken together, results suggest properties may, at least part, mediated stimulation up-regulating potent VEGF/VPF. These genetic changes cooperate epigenetic/environmental hypoxia maximally stimulate Therapeutic disruption result partial angiogenesis, feature enhance therapeutic index endow them anti-tumor effects, out proportion cytostatic monolayer tissue culture.