RESUMO
Numerous chemotherapeutic agents have been shown to have an inhibitory effect on endothelial cell proliferation and migration, and tubule formation. In this study, we examined the antiangiogenic activity of docetaxel. Docetaxel inhibited endothelial cell proliferation and tubule formation in vitro in a dose-dependent fashion. Docetaxel treatment also inhibited angiogenesis in an in vivo Matrigel plug assay. The endothelial stimulating factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor are able to protect endothelial cells from the antiangiogenic properties of docetaxel. This protective effect can be overcome by a recombinant humanized monoclonal antibody directed against VEGF in both in vitro and in vivo models. Similarly, combination of docetaxel with the antiangiogenic agent 2-methoxyestradiol also overcomes the protective effect of VEGF in both in vitro and in vivo models. These data suggest that microenvironmental factors (e.g., local release of VEGF and basic fibroblast growth factor) could play a role in decreasing the antiangiogenic effects of docetaxel, whereas agents such as 2- methoxyestradiol and recombinant humanized monoclonal antibody directed against VEGF may reverse this protective effect.
Assuntos
Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Fatores de Crescimento Endotelial/imunologia , Estradiol/farmacologia , Linfocinas/imunologia , Paclitaxel/análogos & derivados , Paclitaxel/farmacologia , Taxoides , 2-Metoxiestradiol , Inibidores da Angiogênese/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Docetaxel , Sinergismo Farmacológico , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Estradiol/análogos & derivados , Fator 2 de Crescimento de Fibroblastos/fisiologia , Humanos , Camundongos , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Paclitaxel/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Most tumors kill their hosts by the process of metastasis rather than by local growth of the primary mass. A significant factor contributing to the distant invasion of cancer cells is the ability of tumors to produce large numbers of new blood vessels in their midst, known as angiogenesis. This both provides access to nourishment for the primary cancer and enables the cells to escape from the tumor and enter the bloodstream. We have been examining agents that appear to inhibit metastasis and, in particular, angiogenesis. We now report on the ability of the synthetic tetracycline, doxycycline, and the chemically-modified tetracycline, COL-3, to inhibit angiogenesis in a quantitative in vitro assay of angiogenesis, using human umbilical vascular endothelial cells (HUVECs) attached to microcarrier beads.
