Targeting the over-expressed urokinase-type plasminogen activator receptor on glioblastoma multiforme.
A recombinant fusion protein targeting the urokinase-type plasminogen activator receptor (uPAR) and delivering a potent catalytic toxin has the advantage of simultaneously targeting both over-expressed uPAR on glioblastoma cells and on the tumor neovasculature. Such a hybrid protein was synthesized consisting of the noninternalizing amino-terminal fragment (ATF) of urokinase-type plasminogen activator (uPA) for binding, and the catalytic portion of diphtheria toxin (DT) for killing, and the translocation enhancing region (TER) of DT for internalization. The protein was highly selective for human glioblastoma in vitro and in vivo. In vivo, this DT/ATF hybrid called DTAT caused the regression of small subcutaneous uPAR-expressing tumors with minimal toxicity to critical organs. In vitro, DTAT killed only uPAR-positive glioblastoma cell lines and human endothelial cells in the form of the HUVEC cell line. Killing was selective and blockable with specific antibody. DTAT was highly effective against tumor cells cultured from glioblastoma multiforme patients and in vitro mixing experiments combining DTAT with DTIL13 another highly effective anti-glioblastoma agent showed that the mixture was as toxic as the most potent immunotoxin. In this article, we review our progress to date with DTAT.
Rustamzadeh
Edward
E
Department of Neurosurgery, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
Li
Chunbin
C
Doumbia
Sekou
S
Hall
Walter A
WA
Vallera
Daniel A
DA
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D014568:Urokinase-Type Plasminogen Activator / Q000627:therapeutic use*
D004167:Diphtheria Toxin; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; D014568:Urokinase-Type Plasminogen Activator