Inhibition of human malignant glioma growth in vivo by human recombinant plasminogen kringles 1-3

Human malignant gliomas are highly vascularized and aggressive tumors. Angi ogenesis inhibitors have been shown to induce regression of a variety of pr imary and metastatic tumors in vivo. However, their usefulness in treating brain tumors is not well understood. Angiostatin, a multiple kringle (1-4 o f 5)-containing fragment of plasminogen, is one of the highly effective nat ural cryptic angiogenesis inhibitors. In our study, the therapeutic efficac y of non-glycosylated and small molecular size recombinant kringles 1-3 (rP K1-3) was examined in the treatment of brain tumors generated by stereotact ic intracerebral implantation of U-87 human glioma cells in nude mice. Mice bearing tumors 7 days post-implant were treated daily with rPK1-3 (100 mg/ kg) s.c. for 21 days, Treated animals showed suppressed brain tumor growth by greater than 71.2% along with a 3-fold increase of apoptotic index and s uppressed vascularization by 78.9%, without any observable signs of toxicit y, Analysis of bFGF and VEGF expression in the tumors of treated animals us ing immunohistochemical methods showed near complete absence of growth fact ors. Our results indicate that the non-glycosylated, small molecular size r PK1-3 is an efficient tumoristatic agent for the treatment of intracranial human glioma xenografts in mice and might provide new strategies for the tr eatment of brain tumors. Int. J, Cancer 82:694-699, 1999, (C) 1999 Wiley-Li ss, Inc.