In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists.
BACKGROUND
Endothelial cells of human blood vessels (arteries and veins) show high levels of somatostatin subtype-1 receptor (sst(1)). The aim of the present study is to investigate the inhibitory effects of novel somatostatin analogs, highly selective for human sst(1), on in vitro angiogenesis and their modulation of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) expression.


METHODS
Somatostatin analogs BIM-23745 and BIM-23926 were tested for their ability to prevent proliferation and migration of human endothelial HMEC-1 cells, to modulate VEGF and VEGFR-2 expression and to inhibit sprouting of microvessels from cultured human placental vessel explants in fibrin matrix for 28 days.


RESULTS
The somatostatin sst(1 )receptor-selective agonists, BIM-23745 and BIM-23926 showed a suppression of endothelial proliferation (e.g. 10(-6) M BIM-23475, 40.0 +/- 2.1% vs. 100% of controls; 10(-7) M BIM-23926, 55.3 +/- 3.3% vs. 100% of controls), migration (e.g. 10(-7) M BIM-23475, 35.0 +/- 1.56% vs. 100% of controls; 10(-7) M BIM-23926, 53.7 +/- 1.77% vs. 100% of controls) and microvessel sprouting (e.g. 10(-8) M BIM-23475, 42.8 +/- 5.6% vs. 100% of controls; 10(-7) M BIM-23926, 17.2 +/- 11.8% vs. 100% of controls). A small but significant percentage of cells exposed to BIM-23745 and BIM-23926 for 24 h and for 72 h presented typical apoptotic morphology. Moreover, both the analogs significantly inhibit VEGF and VEGFR-2 gene expression in endothelial cells grown for 144 h in a fibrin matrix and the VEGF secretion in conditioned media.


CONCLUSIONS
The inhibition of endothelial activities suggests potential therapeutic utility for administration of somatostatin sst(1 )receptor-selective agonists in the proliferative diseases involving angiogenesis.
Bocci
G
G
University of Pisa, Pisa, Italy. g.bocci@med.unipi.it
Culler
M D
MD
Fioravanti
A
A
Orlandi
P
P
Fasciani
A
A
Colucci
R
R
Taylor
J E
JE
Sadat
D
D
Danesi
R
R
Del Tacca
M
M
D020533:Angiogenesis Inhibitors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D017481:Receptors, Somatostatin / Q000819:agonists / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000819:agonists* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013004:Somatostatin / Q000819:agonists / Q000031:analogs & derivatives*
D020533:Angiogenesis Inhibitors; C519494:BIM 23926; D017481:Receptors, Somatostatin; C101130:somatostatin receptor type 1; D013004:Somatostatin; D040262:Receptors, Vascular Endothelial Growth Factor