Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice.
A fusion protein consisting of human interleukin-13 and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma cell lines in a murine intracranial model. In vitro studies to determine specificity indicated that the protein called DTIL13 was highly selective for human glioblastoma. In vivo, the maximum tolerated dose of DTIL13 was 1 microg/injection given every other day and repeated for 3 days. Doses that exceeded this amount resulted in weight loss and liver damage as determined by histology and enzyme assay. Experiments in IL-4 receptor knockout mice revealed that liver toxicity was receptor-related. This same dose given to nude mice with established U373 MG brain tumors resulted in significant reductions in tumor volume and significantly prolonged survival (p<0.0001). Magnetic resonance imaging (MRI) proved to be extremely useful in (i) determining the ability of DTIL13 to reduce tumor size and (ii) for studying toxicity since diffusion-weighted and gradient echo-weighted MRI revealed that vascular leak syndrome was not a limiting toxicity at this dose. These results suggest that DTIL13 is as effective in an intracranial rodent model as it was in a flank model in previous studies and that DTIL13 might be an effective treatment for glioblastoma multiforme.
Rustamzadeh
Edward
E
Department of Neurosurgery, University of Minnesota Cancer Research Center, Minneapolis, MN 55455, USA.
Hall
Walter A
WA
Todhunter
Deborah A
DA
Low
Walter C
WC
Liu
Haiying
H
Panoskaltsis-Mortari
Angela
A
Vallera
Daniel A
DA
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D038524:Diffusion Magnetic Resonance Imaging; D004167:Diphtheria Toxin / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D018793:Interleukin-13 / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000235:genetics; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments; D016896:Treatment Outcome
D004167:Diphtheria Toxin; D018793:Interleukin-13; D010446:Peptide Fragments; D015847:Interleukin-4