ABSTRACT
The interaction of glycosaminoglycans (GAG) with peptides relies on noncovalent binding to basic amino acid sequences, for which a minimal requirement is a pentapeptide region in the protein and the sulfated and carboxyl region in the GAG. Since such sequences are present in the heparin-binding angiogenic cytokines, including hepatocyte growth factor (HGF), we have postulated that such small peptides may have biological activity. Two basic peptide regions of the beta chain of HGF (RYRNKH512-516, HHRGK645-649) exhibited significant antiangiogenic activity in vivo in the chorioallantoic membrane assay and showed some antiproliferative activity in vitro on normal human brain microvessel endothelial-but not on anchorage-independent endothelial-cells (Kaposi sarcoma). Basic HIV-TAT peptides and scrambled hexapeptides did not show similar activity, except for KRKRKR, indicating sequence specificity of the phenomena. An HGF-derived basic peptide, HHRGK, modulated tumor-induced angiogenesis in vivo by interfering with the morphogenic, but not with the proliferative, phase of the process. These observations suggest small basic peptides as a new class of angiogenesis modulators.
Subject(s)
Brain/blood supply , Endothelium, Vascular/drug effects , Hepatocyte Growth Factor/chemistry , Neovascularization, Physiologic/drug effects , Peptides/pharmacology , Allantois/drug effects , Allantois/physiology , Animals , Brain/cytology , Cell Count , Cell Division/drug effects , Chick Embryo , Chorion/drug effects , Chorion/physiology , Cytokines/pharmacology , Endothelium, Vascular/cytology , Heparin/chemistry , Mice , Mice, SCID , Neovascularization, Physiologic/physiology , Peptides/chemical synthesis , Peptides/chemistry , Protein Structure, Secondary , Protein Structure, Tertiary , Tumor Cells, CulturedABSTRACT
The incidence of staphylococcal mastitis was investigated in 3 large commercial Friesland herds before and after the single intracisternal administration, during the dry-period, of 1 of 4 formulations containing staphylococcal antigens, antibiotics and base alone or in combination. Results suggest that the instillation of vaccine alone and vaccine plus antibiotics into fully involuted quarters very significantly reduced the incidence of staphylococcal mastitis in the subsequent lactation. Compared with antibiotics and base, each administered alone, the vaccine reduced the number of infected quarters in the subsequent lactation by 70,52% and 79,52% respectively, whereas the corresponding values for vaccine plus antibiotics were 62,22% and 71,22% respectively. The difference in results between vaccine alone and vaccine plus antibiotics is statistically insignificant, as is the difference between the results achieved by antiobiotics and base alone. The vaccine plus antibiotics is thought to possess combined therapeutic-preventive activity. The investigation showed, however, that vaccine plus antibiotics consistently protected mastitis negative quarters against new attacks of staphylococcal mastitis during the subsequent lactation period about 1,43, 4,00 and 5,32 times more effectively than did vaccine, antibiotics and base used individually.
