Efficacy of targeted FasL in nasopharyngeal carcinoma

Jian-Hua Li, Wei Shi, Marie Chia, Otto Sanchez-Sweatman, Christopher Siatskas, Dolly Huang, Pierre Busson, Henry J Klamut, Wen-Chen Yeh, Chris Richardson, Brian O'Sullivan, Pat Gullane, Peter Neligan, Jeff Medin, Fei-Fei Liu

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26 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)964 - 973
Number of pages10
JournalMolecular Therapy
Volume8
Issue number6
DOIs
Publication statusPublished - 2003
Externally publishedYes

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