Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice.
A gene splicing technique was used to create a hybrid fusion protein DTAT encoding the 390 amino acid portion of diphtheria toxin (DT(390)), a linker, and the downstream 135-amino terminal fragment portion of human urokinase plasminogen activator. DTAT was assembled to target human glioblastoma cell lines in a murine intracranial model. Previously published in vitro studies demonstrated that DTAT was highly selective and toxic to human glioblastoma cell lines in a flank tumor model. The purpose of this study was to determine the toxicity, specificity and possible therapeutic efficacy of DTAT in an intracranial model. Convection enhanced delivery of DTAT resulted in about a 16-fold increase in maximum tolerated dose. Intracranial administration of DTAT on an every-other-day basis in nude mice with established U87 MG brain tumors resulted in significant reductions in tumor volume and significantly prolonged survival (p < 0.0001). Magnetic resonance imaging proved to be a powerful tool in mice and rats for demonstrating tumor growth in a xenograft intracranial model, assessing the efficacy of DTAT in tumor volume reduction and detecting DTAT-associated intracranial toxicity and vascular damage. These results suggest that the DTAT recombinant fusion protein is highly effective in an intracranial model and DTAT might be an effective treatment for glioblastoma.
Rustamzadeh
Edward
E
Department of Neurosurgery, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
Hall
Walter A
WA
Todhunter
Deborah A
DA
Vallera
Vincent D
VD
Low
Walter C
WC
Liu
Haiying
H
Panoskaltsis-Mortari
Angela
A
Vallera
Daniel A
DA
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007267:Injections; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D011993:Recombinant Fusion Proteins; C471586:diphtheria toxin-urokinase fusion protein, human