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