Adenovirus-mediated hPNPase(old-35) gene transfer as a therapeutic strategy for neuroblastoma.
Current treatment options for neuroblastoma fail to eradicate the disease in the majority of high-risk patients, clearly mandating development of innovative therapeutic strategies. Gene therapy represents a promising approach for reversing the neoplastic phenotype or driving tumor cells to self-destruction. We presently studied the effects of adenovirus-mediated gene transfer of human polynucleotide phosphorylase (hPNPase(old-35)), a 3',5'-exoribonuclease with growth-inhibitory properties, in neuroblastoma cells. Transgene expression was driven by either the cytomegalovirus (CMV) promoter or by a tumor-selective promoter derived from progression elevated gene-3 (PEG-3). Our data demonstrate that efficient adenoviral transduction of neuroblastoma cells and robust transgene expression are feasible objectives, that the PEG-3 promoter is capable of selectively targeting gene expression in the majority of neuroblastoma cells, and that hPNPase(old-35) induces profound growth suppression and apoptosis of malignant neuroblastoma cells, while exerting limited effects on normal neural crest-derived melanocytes. These findings support future applications of hPNPase(old-35) for targeted gene-based therapy of neuroblastoma and suggest that combination with the PEG-3 promoter holds promise for creating a potent and selective neuroblastoma therapeutic. J. Cell. Physiol. 219: 707-715, 2009. (c) 2009 Wiley-Liss, Inc.
Van Maerken
Tom
T
Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
Sarkar
Devanand
D
Speleman
Frank
F
Dent
Paul
P
Weiss
William A
WA
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D002455:Cell Division; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005095:Exoribonucleases / Q000235:genetics* / Q000627:therapeutic use*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000201:enzymology; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000628:therapy; D011991:Receptors, Virus / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D024101:Mitochondrial Proteins
D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005095:Exoribonucleases; D051741:Kruppel-Like Transcription Factors; D011991:Receptors, Virus; D011994:Recombinant Proteins; C568771:CLMP protein, human; C490820:PEG3 protein, human; C476417:PNPT1 protein, human; D024101:Mitochondrial Proteins