Open AccessA peptide derived from the non-receptor-binding region of urokinase plasminogen activator inhibits glioblastoma growth and angiogenesis in vivo in combination with cisplatin
Author(s) -
Kazuhiko Mishima,
Andrew P. Mazar,
Allen M. Gown,
Marilyn Skelly,
Xiang Ji,
Xudong Wang,
Terence R. Jones,
Webster K. Cavenee,
Hui Huang
Publication year - 2000
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.150239497
Subject(s) - angiogenesis , urokinase receptor , cancer research , in vivo , plasminogen activator , urokinase , cisplatin , neovascularization , endothelial stem cell , glioma , tissue plasminogen activator , biology , receptor , in vitro , pharmacology , chemistry , medicine , endocrinology , biochemistry , chemotherapy , microbiology and biotechnology
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 activity of Å6, an octamer capped peptide derived from the non-receptor-binding region of urokinase plasminogen activator. Å6 inhibited human microvascular endothelial cell migration but had no effect on the proliferation of human microvascular endothelial cells or U87MG glioma cellsin vitro . In contrast, Å6 or cisplatin (CDDP) alone suppressed subcutaneous tumor growthin vivo by 48% and 53%, respectively, and, more strikingly, the combination of Å6 plus CDDP inhibited tumor growth by 92%. Such combination treatment also greatly reduced the volume of intracranial tumor xenografts and increased survival of tumor-bearing animals when compared with CDDP or Å6 alone. Tumors from the combination treatment group had significantly reduced neovascularization, suggesting a mechanism involving Å6-mediated inhibition of endothelial cell motility, thereby eliciting vascular sensitivity to CDDP-mediated toxicity. These data suggest that the combination of an angiogenesis inhibitor that targets endothelial cells with a cytotoxic agent may be a useful therapeutic approach.