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Adenovirus-mediated hPNPase(old-35) gene transfer as a therapeutic strategy for neuroblastoma
Tom Van Maerken1, Devanand Sarkar, Frank Speleman
1Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
Abstract:
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.
Insights
Gene therapy using human polynucleotide phosphorylase (hPNPase(old-35)) shows promise for treating high-risk neuroblastoma. This approach effectively suppresses tumor growth and induces cancer cell death while sparing healthy cells.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Neuroblastoma treatment challenges in high-risk patients necessitate novel therapeutic strategies.
- Gene therapy offers a potential avenue for cancer treatment by modifying cellular phenotypes or inducing apoptosis.
- Human polynucleotide phosphorylase (hPNPase(old-35)) is a 3',5'-exoribonuclease with demonstrated growth-inhibitory properties.
Purpose of the Study:
- To investigate the efficacy of adenovirus-mediated gene transfer of hPNPase(old-35) in neuroblastoma cells.
- To evaluate the use of cytomegalovirus (CMV) and progression elevated gene-3 (PEG-3) promoters for transgene expression.
- To assess the selective toxicity of hPNPase(old-35) on neuroblastoma cells versus normal cells.
Main Methods:
- Adenovirus-mediated gene transfer of hPNPase(old-35) into neuroblastoma cells.
- Utilized CMV and PEG-3 promoters to drive transgene expression.
- Assessed transgene expression, cell growth suppression, and apoptosis induction.
- Compared effects on neuroblastoma cells and normal neural crest-derived melanocytes.
Main Results:
- Achieved efficient adenoviral transduction and robust transgene expression in neuroblastoma cells.
- Demonstrated that the PEG-3 promoter selectively targets gene expression in most neuroblastoma cells.
- Observed significant growth suppression and apoptosis in malignant neuroblastoma cells treated with hPNPase(old-35).
- Noted limited effects of hPNPase(old-35) on normal melanocytes.
Conclusions:
- Adenovirus-mediated delivery of hPNPase(old-35) is a feasible approach for neuroblastoma gene therapy.
- The PEG-3 promoter shows potential for selective targeting of neuroblastoma cells.
- hPNPase(old-35) exhibits potent and selective anti-tumor activity, supporting its development as a targeted neuroblastoma therapeutic.
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