We have been collaborating with Drs. David Roberts and Henry C. Krutzsch (Laboratory of Pathology, NCI) studying inhibition of endothelial cell proliferation by synthetic peptide sequences from the matrix protein, thrombospondin-1 (TSP-1). The major goal of this collaboration was to design and test therapeutically useful analogs of these sequences that could block new blood vessel development (angiogenesis) necessary for the growth of primary and metastatic malignant tumors or causing other neovascular pathologies, such as angiogenic retinopathies. The role of this Section has been to assist with the design of peptide analogs, for potential therapeutic use, and to construct polymer conjugates of these peptides as drug delivery vehicles. We have been collaborating with Dr. Diane A. Blake at Tulane University School of Medicine who, has been evaluating the inhibition of retinal angiogenesis by peptides derived from TSP-1 and polysucrose conjugates which this Section has prepared from them. She has carried out these studies in two different models: a bovine retinal explant assay and a rat model of retinopathy of prematurity (ROP). Results indicate that peptides and conjugates derived from the type 1 repeats of thrombospondin-1 may be promising pharmacological agents for treatment of retinal angiogenesis. For in vivo experiments, polysucrose conjugates of a 17-mer peptide proved to be active and, indeed, conferred the advantages of preventing rapid clearance from the vitreous chamber of the bovine eye. - thrombospondin-1, angiogenesis, neovascular pathologies, angiogenic retinopathies, tumor metastasis, retro-inverso peptides
| Yu, H; Tyrrell, D; Cashel, J et al. (2000) Specificities of heparin-binding sites from the amino-terminus and type 1 repeats of thrombospondin-1. Arch Biochem Biophys 374:13-23 |
