Faculty Collaboration Database

Efficacy of targeted FasL in nasopharyngeal carcinoma. Mol Ther 2003 Dec;8(6):964-73

Date

12/11/2003

Pubmed ID

14664799

DOI

10.1016/j.ymthe.2003.08.018

Scopus ID

2-s2.0-0346656768 (requires institutional sign-in at Scopus site)   27 Citations

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.

Author List

Li JH, Shi W, Chia M, Sanchez-Sweatman O, Siatskas C, Huang D, Busson P, Klamut H, Yeh WC, Richardson C, O'Sullivan B, Gullane P, Neligan P, Medin J, Liu FF

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Carcinoma
Caspase 3
Caspase 8
Caspases
Fas Ligand Protein
Genes, Reporter
Genetic Vectors
HeLa Cells
Hepatocytes
Humans
Membrane Glycoproteins
Mice
Mice, SCID
Nasopharyngeal Neoplasms
Up-Regulation