Inhibition of the alpha-ν integrins with a cyclic RGD peptide impairs angiogenesis, growth and metastasis of solid tumours in vivo

Abstract

Anti-angiogenetic cancer therapy is a potential new form for treatment of solid tumours. The a v -integrins (a v b 3 , a v b 5 ) mediate the contact of activated endothelial cells to proteins of the extracellular matrix during tumour angiogenesis as a prerequisite for survival of endothelial cells. The aim of this study was to investigate the effects of application of a methylated cyclic RGDpeptide as an a v -integrin antagonist on angiogenesis, microcirculation, growth and metastasis formation of a solid tumour in vivo. 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 h, the control group received an inactive peptide. Microcirculatory parameters of tumour angiogenesis including functional vessel density, red blood cell velocity, vessel diameter and leucocyte -endothelium interaction were analysed using intravital microscopy. In an additional study the effects on growth and metastasis of subcutaneous A-Mel-3 were quantified. 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 71 ; mean+s.e.m.; P50.05) and increased subsequently in both groups. Red blood cell velocity at day 3 was below values of controls (0.026+0.01 vs 0.12+0.03 mm s 71; P50.05). No differences were observed in vessel diameters and leucocyteendothelium interaction was almost absent in both groups. Furthermore, growth and metastasis of subcutaneous tumours after administration of the cyclic RGD-peptide was significantly delayed in comparison to controls (P50.05). Inhibition of a vintegrins by a cyclic RGD-peptide resulted in significant reduction of functional vessel density, retardation of tumour growth and metastasis in vivo. Taken together, these results implicate RGD-peptides as agents which have anti-tumour and antimetastatic activity in vivo.

αvβ3 and αvβ5 Integrins Bind Both the Proximal RGD Site and Non-RGD Motifs within Noncollagenous (NC1) Domain of the α3 Chain of Type IV Collagen

“…This is supported by the capacity of RGD peptides to inhibit angiogenesis and tumor growth (47)(48)(49), presumably because of their interference with the adhesion and migration of endothelial cells to extracellular matrix proteins (50). In addition, the RGD site may facilitate targeting of ␣3NC1 domain to tumor blood vessels, as has been shown for RGDcontaining conjugates, such as doxorubicin or monoclonal antibodies (51,52).…”

αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer

“…av-integrins on endothelial cells recognize an exposed Arg-Gly-Asp (RGD) sequence within a variety of ECM proteins, including vitronectin, fibrinogen, thrombospondin, proteolysed collagen, von Willenbrand factor and osteopontin (Hynes, 1992;Stupack and Cheresh, 2002;Ru¨egg et al, 2004). Several agents such as blocking antibodies or synthetic RGD-containing peptides directed against av-integrins have been generated and shown to inhibit in vitro endothelial tube formation or microvessel formation (Janssen et al, 2002;Buerkle et al, 2002). To this regard, we reported that specific a v b 3 antagonists decreased the viability and growth of MCF-7 cells forced to overexpress CYR61, an angiogenic regulator that is differentially expressed in invasive human breast cancer cells (Tsai et al, 2000;Menendez et al, 2004).…”

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

“…30,32 Our data are consistent with previous observations suggesting that the effect of adding TNF to melphalan-based ILP is due principally to increased accumulation of melphalan in tumor tissue. 22 They further suggest that the same mechanism underlies the enhanced response rates achieved by the addition of cilengitide to ILP.…”

“…[17][18][19] Cilengitide disrupts VE-cadherin localization at cell junctions, and increases endothelial monolayer permeability 20 and disrupts angiogenesis in vitro 21 and in vivo. 22 In a tumor-induced CAM assay, it inhibits cell-matrix contact and angiogenesis. 23 Co-administration of this anti-integrin improved the efficacy of radioimmunotherapy in breast cancer xenograft 24 and glioblastoma orthotopic xenograft model.…”