Intracranial elimination of human glioblastoma brain tumors in nude rats using the bispecific ligand-directed toxin, DTEGF13 and convection enhanced delivery.
A bispecific ligand-directed toxin (BLT) consisting of human interleukin-13, epithelial growth factor, and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma. In vitro, DTEGF13 selectively killed the human glioblastoma cell line U87-luc as well as other human glioblastomas. DTEGF13 fulfilled the requirement of a successful BLT by having greater activity than either of its monospecific counterparts or their mixture proving it necessary to have both ligands on the same single chain molecule. Aggressive brain tumors established intracranially (IC) in nude rats with U87 glioma genetically marked with a firefly luciferase reporter gene were treated with two injections of DTEGF13 using convection enhanced delivery resulting in tumor eradication in 50% of the rats which survived with tumor free status at least 110 days post tumor inoculation. An irrelevant BLT control did not protect establishing specificity. The bispecific DTEGF13 MTD dose was measured at 2 microg/injection or 0.5 microg/kg and toxicity studies indicated safety in this dose. Combination of monospecific DTEGF and DTIL13 did not inhibit tumor growth. ELISA assay indicated that anti-DT antibodies were not generated in normal immunocompetent rats given identical intracranial DTEGF13 therapy. Thus, DTEGF13 is safe and efficacious as an alternative drug for glioblastoma therapy and warrants further study.
Oh
Seunguk
S
Section on Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Masonic Cancer Center, MMC: 367, Minneapolis, MN, 55455, USA.
Ohlfest
John R
JR
Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Todhunter
Deborah A
DA
Section on Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Masonic Cancer Center, MMC: 367, Minneapolis, MN, 55455, USA.
Vallera
Vincent D
VD
Section on Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Masonic Cancer Center, MMC: 367, Minneapolis, MN, 55455, USA.
Hall
Walter A
WA
Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, NY, USA.
Chen
Hua
H
Section on Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Masonic Cancer Center, MMC: 367, Minneapolis, MN, 55455, USA.
Vallera
Daniel A
DA
Section on Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Masonic Cancer Center, MMC: 367, Minneapolis, MN, 55455, USA. valle001@umn.edu.
D000818:Animals; D000918:Antibody Specificity; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008024:Ligands; D008099:Liver / Q000187:drug effects; D008156:Luciferases / Q000235:genetics; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics* / Q000633:toxicity*; D023041:Xenograft Model Antitumor Assays
C525855:DTEGF13 cytotoxin; D007074:Immunoglobulin G; D008024:Ligands; D011993:Recombinant Fusion Proteins; D008156:Luciferases