Convection-enhanced delivery of tumor necrosis factor-related apoptosis-inducing ligand with systemic administration of temozolomide prolongs survival in an intracranial glioblastoma xenograft model.
Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent activator of cell death, preferentially killing neoplastic cells over normal cells, the efficacy of TRAIL for the treatment of glioma might be limited due to cellular resistance and, importantly, poor distribution after systemic administration. TRAIL and temozolomide (TMZ) were recently shown to have a synergistic antitumor effect against U87MG glioma cells in vitro. Convection-enhanced delivery (CED) can effectively distribute TRAIL protein throughout a brain tumor mass. In this study, we evaluated CED of TRAIL, alone and in conjunction with systemic TMZ administration, for antitumor efficacy. CED of TRAIL demonstrated safe and effective distribution in both normal brain and a U87MG intracranial xenograft model. Individually, both CED of TRAIL and systemic TMZ administration prolonged survival in tumor-bearing rats. However, the combination of these two treatments was significantly more effective than either treatment alone. CED of TRAIL in conjunction with systemic TMZ treatment is a promising strategy for the treatment of malignant gliomas.
Brain Tumor Research Center, Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94103, USA.
Ryuta
R
Saito
John R
JR
Bringas
Amith
A
Panner
Matyas
M
Tamas
Russell O
RO
Pieper
Mitchel S
MS
Berger
Krystof S
KS
Bankiewicz
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018481:Convection; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D011923:Rats, Nude; D011994:Recombinant Proteins / Q000008:administration & dosage; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077204:Temozolomide; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505655:Tnfsf10 protein, rat; D014409:Tumor Necrosis Factor-alpha; D003606:Dacarbazine; D000077204:Temozolomide