Richard P. Kitson

The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions.

Bruce S. McEwen , Christine A. Biron , Kenneth W. Brunson , Karen Bulloch , William H. Chambers , Firdaus S. Dhabhar , Ronald H. Goldfarb , Richard P. Kitson , Andrew H. Miller , Robert L. Spencer , Jay M. Weiss d a Laboratory of Neuroendocrinology, Rockefeller UniÕersity, 1230 York AÕenue, Box 165, New York, NY 10021, USA b DiÕision of Biology and Medicine, Brown UniÕersity, ProÕidence, RI, USA c Pittsburgh Cancer Institute, UniÕersity of Pittsburgh, School of Medicine, Pittsburgh, PA, USA d Department of Psychiatry and BehaÕioral Sciences, Emory UniÕersity School of Medicine, Atlanta, GA, USA

A KDR-binding peptide (ST100,059) can block angiogenesis, melanoma tumor growth and metastasis in vitro and in vivo

A major goal of treatment strategies for cancer is the development of agents which can block primary tumor growth and development as well as the progression of tumor metastasis without any treatment associated side effects. Using mini peptide display (MPD) technology, we generated peptides that can bind to the human vascular endothelial growth factor (VEGF) receptor KDR. These peptides were evaluated for their ability to block angiogenesis, tumor growth and metastasis in vitro and in vivo. A D-amino acid peptide with high serum stability (ST100,059) was found to have the most potent activity in vitro as indicated by inhibition of VEGF stimulation of endothelial cells. It was also found to be the most active of the series in blocking VEGF-mediated activity in vivo, as measured in Matrigel-filled angioreactors implanted in mice. ST100,059 blocks VEGF-induced MAPK phosphorylation, as well as inhibits VEGF-induced changes in gene expression in HUVEC cells. In in vivo studies, treatment of female C57BL/6 mice inoculated with B16 mouse melanoma cells with ST100,059 resulted in a dose-dependent decrease in tumor volume and lung metastasis as compared to control groups of animals receiving vehicle alone. These studies demonstrate that by using MPD, peptides can be identified with enhanced affinity relative to those discovered using phage display. Based on these studies we have identified one such peptide ST100,059 which can effectively block tumor growth and metastasis due to its anti-angiogenic effects and ability to block intracellular signaling pathways involved in tumor progression.