Carbohydrate Mimicking Peptides as Inhibitors of Angiogenesis and Metastasis
Abstract
The tumor cell-endothelial-cell (EC) interaction, specifically that between E-selectin on EC and carbohydrate ligands on leukocytes and tumor cells, has recently emerged as a promising target for cancer therapy. The carbohydrate structures sialyl-Lewis X (SA-LeX), sialyl-Lewis a (SA-Le(a)) and Lewis Y (LeY) are the key factor underlying the metastatic potential of carcinoma cells. The proposed studies explored the possibility of generating peptide mimetics to interrupt adhesion of tumor cells to vascular endothelium and thereby significantly reduce metastatic spread in analogy with reduction of neutrophil recruitment in chronic inflammation. We have identified a panel of 12-mer peptides from a random peptide library using monoclonal antibodies (MAbs) specific for human tumor-associated carbohydrate antigens, i.e., SA-Le(a), SA-LeX and LeY, and the peptides were proven to retain a carbohydrate-like conformation. Most importantly they can block selectin function in vivo. In addition to the originally proposed studies, we have identified a panel of peptides mimicking E-selectin ligand(s) using E-selectin-IgG immunoglobulin fusion protein and applied peptide array based on the selected peptides to characterize amino acids important for MAb/E-selectin interaction as well as to identify peptides with increased binding ability. We established syngeneic murine models and are in a process of applying the identified peptides as anti-adhesion therapy against development of metastasis. These studies provide significant information pertinent to new strategies for therapeutic intervention for human cancer and insight into the role of adhesion and carbohydrate determinants in the metastatic process.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 1998
- Accession Number
- ADA352072
Entities
People
- Magdalena Blaszczyk-thurin
Organizations
- University of Pennsylvania