Retinal neovascularization is a major cause of blindness in such disorders as retinopathy of prematurity, proliferative diabetic retinopathy and senile macular degeneration. Because ligation of vitronectin receptor-type integrins appears to be required for the survival and maturation of newly formed but not quiescent blood vessels in several vascular beds including the retina, blockade of this downstream adhesion receptor system was investigated. In a mouse model of hypoxia-induced retinal neovascularization twice daily administration of 1 to 20 mg cyclic alpha v-integrin antagonist peptide per kilogram of body weight reduced capillary proliferation in a dose-dependent fashion--maximum 76%--without obvious side effects. A cyclic control peptide displayed no inhibitory effect on neovascularization. These findings indicate that systemic application of vitronectin receptor antagonists appears to be clinically feasible and is efficient in preventing retinal neovascularization and superior to cytokine-blocking strategies.
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.
Expression of the avb3 integrin is upregulated on sprouting endothelia. Systemic application of antibody or peptidic inhibitors of avb3 function disrupts tumor angiogenesis and reduces growth and invasiveness of human tumors in animal models. We systematically investigated avb3 expression on tumor-associated vessels of 4 different human epithelial tumors and the corresponding normal tissues by means of immunohistochemistry on frozen sections using the avb3-complex specific monoclonal antibody LM609. Variable levels of LM609 staining were found in all carcinoma lesions. A considerable number of tumor tissues (35/50) expressed avb3 on more than 50% of their vessels. Inflammatory infiltrates and the possibly hypoxic conditions near necrotic areas of tumors were accompanied by an increased avb3 expression. Remarkably, the vasculature in apparently normal tissue also stained for avb3. However, the percentages of stained vessels and their staining intensity were lower than in neoplastic tissues. Besides the vascular avb3 expression, several extravascular cell types stained positive, in both normal and tumor specimens. Taken together, our findings show a considerable number of colon, pancreas, lung and breast carcinoma lesions with many avb3-expressing vessels that could be targets for anti-avb3-therapy. Int.
To gain insight into the developmental program of nerve growth factor (NGF) receptor expression, the binding of [125I] beta NGF to frozen chick sections was investigated autorradiographically between embryonic day 3 (E3) and post‐hatching day 3. Strong NGF receptor expression was observed as early as E4, throughout embryonic development and in the post‐hatching period at the classical NGF target sites: the paravertebral sensory and sympathetic ganglia, the paraaortal sympathetic ganglia as well as the cranial sensory ganglia with neurons of neural crest origin and their respective nerves. Only weak [125I] beta NGF binding was observed during a restricted time span in the parasympathetic ciliary ganglion. Clear differences were observed in the intensity and in the developmental time course of [125I] beta NGF binding to the dorsomedial and ventrolateral aspects of the dorsal root ganglia. NGF receptors were also found to be expressed on central axons of the dorsal root entry zone and the dorsal tract in the spinal cord. A transient expression of specific NGF binding sites of the same high affinity as measured at the classical NGF targets, was detected in the lateral motor column and in muscle at the time of motoneuron synapse formation and elimination.
Expression of the alpha vbeta3 integrin is upregulated on sprouting endothelia. Systemic application of antibody or peptidic inhibitors of alpha vbeta3 function disrupts tumor angiogenesis and reduces growth and invasiveness of human tumors in animal models. We systematically investigated alpha vbeta3 expression on tumor-associated vessels of 4 different human epithelial tumors and the corresponding normal tissues by means of immunohistochemistry on frozen sections using the alpha vbeta3-complex specific monoclonal antibody LM609. Variable levels of LM609 staining were found in all carcinoma lesions. A considerable number of tumor tissues (35/50) expressed alpha vbeta3 on more than 50% of their vessels. Inflammatory infiltrates and the possibly hypoxic conditions near necrotic areas of tumors were accompanied by an increased alpha vbeta3 expression. Remarkably, the vasculature in apparently normal tissue also stained for alpha vbeta3. However, the percentages of stained vessels and their staining intensity were lower than in neoplastic tissues. Besides the vascular alpha vbeta3 expression, several extravascular cell types stained positive, in both normal and tumor specimens. Taken together, our findings show a considerable number of colon, pancreas, lung and breast carcinoma lesions with many alpha vbeta3-expressing vessels that could be targets for anti-alpha vbeta3-therapy.
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