Inhibition of the alpha-nu integrins with a cyclic RGD peptide impairs angiogenesis, growth and metastasis of solid tumours in vivo.
Anti-angiogenetic cancer therapy is a potential new form for treatment of solid tumours. The alpha(v)-integrins (alpha(v)beta3, alpha(v)beta5) 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 RGD-peptide as an alpha(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(-1); mean +/- s.e.m.; P<0.05) 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 x s(-1); P<0.05). No differences were observed in vessel diameters and leucocyte-endothelium 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 (P<0.05). Inhibition of alpha(v)-integrins 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 anti-metastatic activity in vivo.
Buerkle
M A
MA
Institute for Surgical Research, Klinikum Grosshadern, Marchioninistrasse 15, Ludwig-Maximilians-University, 81377 Munich, Germany.
Pahernik
S A
SA
Sutter
A
A
Jonczyk
A
A
Messmer
K
K
Dellian
M
M
D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006224:Cricetinae; D004727:Endothelium / Q000166:cytology / Q000473:pathology; D007263:Infusions, Parenteral; D039423:Integrin alpha1; D007962:Leukocytes / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000473:pathology*; D008833:Microcirculation; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000473:pathology*
D015703:Antigens, CD; D000970:Antineoplastic Agents; D039423:Integrin alpha1; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid