Antiangiogenetic cancer therapy by inhibition of the integrin alpha(v)beta(3) using a cyclic peptide

Backround: Antiangiogenetic cancer therapy, inhibition of the formation of new blood vessels, is a potential new form for treatment of solid tumors. T he alpha(v)-integrins (alpha(v)beta(3), alpha(v)beta(5)) mediate the contac t of activated endothelial cells to proteins of the extracellular matrix, t hus their survival during angiogenesis. The aim of this study was to invest igate the effects of inhibition of alpha(v)-integrins by a cyclic RGD-pepti de on angiogenesis and microcirculation of tumors in vivo. Material and methods: Experiments were performed in the dorsal skinfold cha mber preparation of Syrian Golden hamsters (45 - 55 g body weight) bearing the amelanotic hamster melanoma A-Mel-3. Animals were treated with a cyclic RGD-peptide from day 1 to day 13 after tumor implantation (30 mg/kg body w eight i.p. every 12 hours). The control group received an inactive peptide. Microcirculatory parameters including functional vessel density (FVD), red blood cell velocity (VRBC), vessel diameter (d) and leukocyte endothelium interaction were analyzed using intravital microscopy. In an additional stu dy the effects on subcutaneous tumor growth were quantified. Results: Functional vessel density was significantly reduced on day 3 in tr eated animals in comparison to controls (37.2 +/- 12.1 vs. 105.2 +/- 11.2 c m2/cm; mean +/- s.e.m.; p < 0.05), and increased subsequently in both group s. Similar, vRBC at day 3 was markedly below values of controls (0.04 +/- 0 .01 vs. 0.12 +/- 0.03 mm/s; p < 0.05). No differences were observed in vess el diameters. Leukocyte-endothelium interaction was almost absent in both g roups, and growth of subcutaneous tumors in the RGD-group was delayed for 3 .5 days in comparison to controls. Conclusion: Inhibition of alpha(v)-integrins by a cyclic RGD-peptide result ed in significant delay of early tumor angiogenesis, associated with retard ation of tumor growth were quantified.