Accession Number:

ADA434632

Title:

Development of Peptide Antagonists of Chemokine Receptors Involved in Breast Cancer Metastasis

Descriptive Note:

Final rept. 1 Sep 2003-28 Feb 2005

Corporate Author:

TORREY PINES INST FOR MOLECULAR STUDIESSAN DIEGO CA

Personal Author(s):

Report Date:

2005-03-01

Pagination or Media Count:

10.0

Abstract:

Breast cancer cells where shown to express functionally active chemokine receptors that may promote metastasis, and an anti-human CXCR4 chemokine receptor monoclonal antibody was found to reduce the level of lung metastasis by 61-68 percent. Based on these findings supporting the role for chemokine ligand-receptor interactions in promoting metastasis of breast cancer, we develop small molecule antagonists to CXCR4. This was accomplished by screening in a competitive assay synthetic combinatorial libraries SCLs made up of D-amino acid peptides for their ability to antagonize CXCR4 receptor function using HeLa cells and PBMC cells used as standard, and breast cancer cells MDA-MB-231 and DU4475, known to express CXCR4, and a monoclonal antibody anti-CXCR4 known to block chemotaxis induced by CXCL12 formerly known as SDF-1. The SCL approach, particularly when generated in a positional scanning PS format, allows the direct identification of the key residues of active peptide sequences from the library screening. Following the screening of a library, candidate sequences were synthesized and their inhibitory activity on the binding of anti-CXCR4 antibody was evaluated as well as their ability to abrogate the migratory response of cells inducted by SDF-1.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE