? Recent clinical results with angiogenesis-inhibiting biopharmaceuticals have validated this class of ? therapeutics as important anti-cancer agents. The most promising therapeutic candidates to date interfere with proangiogenic stimulation by VEGF. Our collaborators (under a CRADA) at the National Cancer Institute have recently demonstrated that the adrenomedullin gene-related peptide, PAMP, exhibits proangiogenic activity at picomolar concentrations, whereas VEGF and other """"""""classical"""""""" angiogenic factors mediate a comparable effect at nanomolar concentrations. Human microvascular endothelial cells express PAMP receptors and respond to exogenous addition of PAMP by increasing migration and cord formation. Exposure of endothelial cells to PAMP increases gene expression of other angiogenic factors such as adrenomedullin, VEGF, bFGF, and PDGF-C. In addition, the peptide fragment PAMP(12-20) acts as a PAMP antagonist and inhibits tumor cell-induced angiogenesis in vivo and reduces tumor growth in xenograft models. Although this work demonstrated that PAMP(12-20) can strongly inhibit both angiogenesis and tumor growth in vivo, the therapeutic potential of this novel antiangiogenic molecule could be dramatically improved by stabilizing it against degradation and renal clearance. PAMP and its derivatives are rapidly degraded in vivo by neprilysin. Because neprilysin only degrades peptides <3,000 daltons, we propose to stabilize the PAMP-antagonist by increasing its molecular weight to >10,000 daltons through the addition of a polyethylene glycol chain. This approach is likely to increase the activity of the PAMP agonist by several orders of magnitude and could lead to a novel antiangiogenesis-based cancer treatment. ? ?
