Inhibition of human malignant glioma growth in vivo by human recombinant plasminogen kringles 1-3.
Human malignant gliomas are highly vascularized and aggressive tumors. Angiogenesis inhibitors have been shown to induce regression of a variety of primary and metastatic tumors in vivo. However, their usefulness in treating brain tumors is not well understood. Angiostatin, a multiple kringle (1-4 of 5)-containing fragment of plasminogen, is one of the highly effective natural cryptic angiogenesis inhibitors. In our study, the therapeutic efficacy of non-glycosylated and small molecular size recombinant kringles 1-3 (rPK1-3) was examined in the treatment of brain tumors generated by stereotactic 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 suppressed vascularization by 78.9%, without any observable signs of toxicity. Analysis of bFGF and VEGF expression in the tumors of treated animals using immuno-histochemical methods showed near complete absence of growth factors. Our results indicate that the non-glycosylated, small molecular size rPK1-3 is an efficient tumoristatic agent for the treatment of intracranial human glioma xenografts in mice and might provide new strategies for the treatment of brain tumors.
Joe
Y A
YA
Cancer Research Institute, The Catholic University of Korea, Seoul, Korea.
Hong
Y K
YK
Chung
D S
DS
Yang
Y J
YJ
Kang
J K
JK
Lee
Y S
YS
Chang
S I
SI
You
W K
WK
Lee
H
H
Chung
S I
SI
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D005910:Glioma / Q000473:pathology*; D006801:Humans; D018082:Kringles / Q000235:genetics*; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000517:prevention & control*; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000627:therapeutic use; D010958:Plasminogen / Q000235:genetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005346:Fibroblast Growth Factors; D010958:Plasminogen