Effekt einer Antagonisierung der alpha- v-Integrine auf Angiogenese, Wachstum und Metastasierung solider Tumoren in vivo
Introduction: Antiangiogenetic cancer therapy is a potential new form for treatment of solid tumors. The alpha-v-integrins ( avb3, avb5) mediate the contact of activated endothelial cells to proteins of the extracellular matrix during tumor angiogenesis as a prerequisite for survival of endothelial cells. The aim of this study was to investigate the effects of inhibition of alpha-v-integrins with a methylated cyclic RGD-peptide on angiogenesis, microcirculation, growth and metastasis formation of a solid tumor in vivo. Methods: Experiments were performed in the dorsal skinfold preparation of Syrian Golden hamsters bearing the amelanotic hamster melanoma A-Mel-3. Animals were injected intraperitoneally with a methylated cyclic RGD-peptide every 12 hours, the control group received an inactive peptide. Microcirculatory parameters of tumor angiogenesis including functional vessel density, red blood cell velocity (vRBC), vessel diameter and leukocyte endothelium interaction were analyzed using intravital microscopy. In an additional study the effects on growth and metastasis of subcutaneous A-Mel-3 were quantified. Results: Functional vessel density was markedly reduced on day 3 in treated animals compared to controls (37.2+/-12.1 vs. 105.2+/-11.2 cm-1; mean+/-SEM; P < 0.05), and increased subsequently in both groups. vRBC at day 3 was below values of controls (0.026+/-0.01 vs. 0.12+/-0.03 mm/s; P < 0.05). No differences were observed in vessel diameters and leukocyte-endothelium interaction was almost absent in both groups. Furthermore, growth and metastasis of subcutaneous tumors after administration of the cyclic RGD-peptide was significantly delayed in comparison to controls (P < 0.05). Conclusion: Inhibition of alpha-v-integrins by a cyclic RGD-peptide resulted in significant delay of early tumor angiogenesis, associated with retardation of tumor growth and metastasis in vivo. Application of cyclic RGD-peptides may thus be a promising approach for antiangiogenic therapy of solid tumors
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