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Connexin 26 enhances the bystander effect in HSVtk/GCV gene therapy for human bladder cancer by adenovirus/PLL/DNA gene delivery

Gene Therapy volume 8, pages 139–148 (2001)Cite this article

Abstract

Herpes simplex thymidine kinase/ganciclovir (HSVtk/GCV) gene therapy has been used for the treatment of a variety of cancers. Its efficacy is enhanced by the bystander effect that helps overcome the delivery problems commonly observed in current gene therapy. Connexins encode proteins that produce gap junctions, which enable intercellular communication and the bystander effect. We previously demonstrated that decreased Cx 26 expression and loss of gap junctional intercellular communication were associated with human bladder cancer. To investigate the efficacy of the bystander effect in HSVtk/GCV gene therapy, the Cx 26 gene was introduced into UM-UC-3 and UM-UC-14 bladder cancer cell lines by an adenovirus poly-L-lysine conjugate using a multigenic expression plasmid that expressed both the HSVtk and Cx 26 genes. We found significantly increased cytotoxicity in HSVtk/GCV gene therapy after introduction of the HSVtk and Cx 26 genes together compared with the cytotoxicity seen after introduction of the HSVtk gene and LacZ genes in vitro and in vivo. Cytotoxicity correlated with Cx 26 expression and the induction of functional gap junctions. This study indicates that combination gene therapy with co-expression of the HSVtk and Cx 26 genes potentiates HSVtk/GCV gene therapy through the bystander effect.

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Acknowledgements

We thank Ms Sandra A Wiehle for her help in Adv/PLL conjugate preparation. This work was supported in part by a grant from the WM Keck Center for Cancer Gene Therapy.

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Author notes

  1. M Liebert

    Present address: National Institutes for Diabetes and Digestive and Kidney Disorders at the National Institute of Health, Bethesda, 20892, MD, USA

Authors and Affiliations

  1. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Tanaka, GC Fraizer, J De La Cerda & HB Grossman

  2. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    RJ Cristiano

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Tanaka, M., Fraizer, G., De La Cerda, J. et al. Connexin 26 enhances the bystander effect in HSVtk/GCV gene therapy for human bladder cancer by adenovirus/PLL/DNA gene delivery. Gene Ther 8, 139–148 (2001). https://doi.org/10.1038/sj.gt.3301367

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