Efficacy of targeted FasL in nasopharyngeal carcinoma.
We have successfully achieved selective gene expression in human nasopharyngeal carcinoma (NPC) by exploiting the presence of the Epstein-Barr virus (EBV), utilizing a transcriptional targeting strategy (J. H. Li et al., 2002, Cancer Res. 62: 171). Building on this platform, we have generated a novel DeltaE1 adenoviral vector mediating the expression of a mutant noncleavable form of the FasL gene (HUGO-approved symbol TNFSF6) (ad5oriP.ncFasL). We observe that this therapy induces significant cytotoxicity in the EBV-positive NPC cell line C666-1, mediated by the induction of caspase-dependent apoptosis. The addition of ionizing radiation therapy (RT) causes additional cytotoxicity. Ex vivo infection of C666-1 cells with adv.oriP.ncFasL completely prevents tumor formation in SCID mice followed for up to 100 days. The combination of intratumoral adv.oriP.ncFasL with RT causes regression of established nasopharyngeal xenograft tumors for 2 weeks' duration. Systemic delivery of this targeted strategy achieves 50-fold higher gene expression in nasopharyngeal tumors than in normal organs. Intravenously injected adv.oriP.ncFasL results in mild perturbation of liver function that returns to normal 2 weeks after initial therapy. These results demonstrate the efficacy of our EBV-specific targeting strategy, which allows the potentially safe and effective utilization of a highly potent membrane-based apoptotic gene.
Li
Jian-Hua
JH
Ontario Cancer Institute, University of Toronto, Toronto, Ontario MS 1A1, Canada.
Shi
Wei
W
Chia
Marie
M
Sanchez-Sweatman
Otto
O
Siatskas
Christopher
C
Huang
Dolly
D
Busson
Pierre
P
Klamut
Henry
H
Yeh
Wen-Chen
WC
Richardson
Chris
C
O'Sullivan
Brian
B
Gullane
Pat
P
Neligan
Peter
P
Medin
Jeff
J
Liu
Fei-Fei
FF
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy*; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000187:drug effects; D053222:Fas Ligand Protein; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000493:pharmacokinetics / Q000633:toxicity; D006367:HeLa Cells; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000493:pharmacokinetics*; D051379:Mice; D016513:Mice, SCID; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy*; D015854:Up-Regulation
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases