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Updated: Aug 15, 2026
Transposon Mediated Integration of Plasmid DNA into the Subventricular Zone of Neonatal Mice to Generate Novel Models of Glioblastoma
Published on: February 22, 2015
Single-shot, multicycle suicide gene therapy by replication-competent retrovirus vectors achieves long-term survival
Chien-Kuo Tai1, Wei Jun Wang, Thomas C Chen
1Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Abstract:
Achieving therapeutically efficacious levels of gene transfer in tumors has been a major obstacle for cancer gene therapy using replication-defective virus vectors. Recently, replicating viruses have emerged as attractive tools for cancer therapy, but generally achieve only transitory tumor regression. In contrast to other replicating virus systems, transduction by replication-competent retrovirus (RCR) vectors is efficient, tumor-selective, and persistent. Correlating with its efficient replicative spread, RCR vector expressing the yeast cytosine deaminase suicide gene exhibited remarkably enhanced cytotoxicity in vitro after administration of the prodrug 5-fluorocytosine. In vivo, RCR vectors replicated throughout preestablished primary gliomas without spread to adjacent normal brain, resulting in profound tumor inhibition after a single injection of virus and single cycle of prodrug administration. Furthermore, stable integration of the replicating vector resulted in persistent infection that achieved complete transduction of ectopic glioma foci that had migrated away from the primary tumor site. Thus, efficient and stable integration of suicide genes represents a unique property of the RCR vector that achieved multiple cycles of synchronous cell killing upon repeated prodrug administration, resulting in chronic suppression of tumor growth and prolonged survival.
Insights
Replication-competent retrovirus (RCR) vectors efficiently target gliomas, delivering suicide genes for potent cancer therapy. Stable integration leads to persistent infection and chronic tumor suppression, prolonging survival.
Area of Science:
- Oncology
- Virology
- Gene Therapy
Background:
- Gene transfer into tumors is challenging for cancer gene therapy.
- Replicating viruses offer potential but often yield temporary tumor regression.
- Replication-competent retrovirus (RCR) vectors demonstrate efficient, tumor-selective, and persistent transduction.
Purpose of the Study:
- To evaluate the efficacy of RCR vectors for glioma treatment.
- To assess the tumor-selective replication and gene delivery of RCR vectors.
- To determine the therapeutic potential of RCR-mediated suicide gene therapy in vivo.
Main Methods:
- RCR vectors expressing the yeast cytosine deaminase suicide gene were constructed.
- In vitro cytotoxicity was assessed after 5-fluorocytosine (prodrug) administration.
- In vivo studies involved injecting RCR vectors into preestablished gliomas in mice.
Main Results:
- RCR vectors showed enhanced in vitro cytotoxicity with the suicide gene and prodrug.
- In vivo, RCR vectors replicated within gliomas without affecting normal brain tissue.
- A single RCR injection and prodrug cycle led to significant tumor inhibition.
- Stable vector integration resulted in persistent infection and complete transduction of migrated glioma foci.
- Repeated prodrug administration with RCR vectors achieved chronic tumor growth suppression and prolonged survival.
Conclusions:
- RCR vectors are efficient and tumor-selective tools for gene therapy.
- Stable integration of suicide genes via RCR vectors enables persistent therapeutic effects.
- RCR-mediated suicide gene therapy offers a promising strategy for chronic glioma suppression and improved survival.
