A peptide derived from the non-receptor-binding region of urokinase plasminogen activator inhibits glioblastoma growth and angiogenesis in vivo in combination with cisplatin

The urokinase plasminogen activator system is involved in angiogenesis and tumor growth of malignant gliomas, which are highly neovascularized and so may be amenable to antiangiogenic therapy. In this paper, we describe the a ctivity of Angstrom 6, an octamer capped peptide derived from the non-recep tor-binding region of urokinase plasminogen activator. Angstrom 6 inhibited human microvascular endothelial cell migration but had no effect on the pr oliferation of human microvascular endothelial cells or U87MG glioma cells in vitro. In contrast, Angstrom 6 or cisplatin (CDDP) alone suppressed subc utaneous tumor growth in vivo by 48% and 53%, respectively, and, more strik ingly, the combination of Angstrom 6 plus CDDP inhibited tumor growth by 92 %. Such combination treatment also greatly reduced the volume of intracrani al tumor xenografts and increased survival of tumor-bearing animals when co mpared with CDDP or Angstrom 6 alone. Tumors from the combination treatment group had significantly reduced neovascularization, suggesting a mechanism involving Angstrom 6-mediated inhibition of endothelial cell motility, the reby eliciting vascular sensitivity to CDDP-mediated toxicity. These data s uggest that the combination of an angiogenesis inhibitor that targets endot helial cells with a cytotoxic agent may be a useful therapeutic approach.