The role of cellular- and prodrug-associated factors in the bystander effect induced by the Varicella zoster and Herpes simplex viral thymidine kinases in suicide gene therapy (original) (raw)

Cancer Gene Therapy volume 7, pages 1456–1468 (2000)Cite this article

Abstract

To investigate the factors influencing the bystander effect — a key element in the efficacy of suicide gene therapy against cancer — we compared the effect triggered by four extremely efficient gene/prodrug combinations, i.e., VZV_tk_/BVDU, the thymidine kinase of Varicella zoster virus associated with (E)-5-(2-bromovinyl)-2′-deoxyuridine; VZV_tk_/BVaraU, the same enzyme associated with (E)-5-(2-bromovinyl)-1-β-D-arabinofuranosyluracil; HSV_tk_/BVDU, the association of the Herpes simplex virus thymidine kinase with BVDU; and the classical HSV_tk_/GCV (ganciclovir) paradigm. The cells used, the human MDA-MB-435 breast cancer, and the rat 9L glioblastoma lines were equally sensitive in vitro to these four associations. In both cell types, the combinations involving pyrimidine analogues (BVDU, BVaraU) displayed a smaller bystander killing than the combination involving the purine analogue (GCV). In addition, the bystander effect induced by all the tk/prodrug systems was reduced in MDA-MB-435 cells in comparison to 9L cells; albeit, the viral kinases were produced at a higher level in the breast cancer cells. All systems induced apoptotic death in the two cell types, but the MDA-MB-435 cells, deprived of connexin 43, were noncommunicating in striking contrast with the 9L cells. That functional gap junctions have to be increased in order to improve the breast cancer cell response to suicide gene therapy was demonstrated by transducing the Cx43 gene: this modification enhanced the bystander effect associated in vitro with GCV treatment and, by itself, decreased the tumorigenicity of the untreated cells. However, the noncommunicating MDA-MB-435 cells triggered a significant bystander effect both in vitro and in vivo with the HSV_tk_/GCV system, showing that communication through gap junctions is not the only mechanism involved. Cancer Gene Therapy (2000) 7, 1456–1468

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Authors and Affiliations

  1. Laboratory of Fundamental Virology and Immunology, Institute of Pathology, B23, University of Liège, Liège, 4000, Belgium
    Christine Grignet-Debrus & Claire-Michelle Calberg-Bacq
  2. Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Faculty of Medicine, Free University of Brussels, Brussels, 1070, Belgium
    Vincent Cool, Nathalie Baudson & Thierry Velu

Authors

  1. Christine Grignet-Debrus
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  2. Vincent Cool
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  3. Nathalie Baudson
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  4. Thierry Velu
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  5. Claire-Michelle Calberg-Bacq
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Correspondence toChristine Grignet-Debrus.

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Grignet-Debrus, C., Cool, V., Baudson, N. et al. The role of cellular- and prodrug-associated factors in the bystander effect induced by the Varicella zoster and Herpes simplex viral thymidine kinases in suicide gene therapy.Cancer Gene Ther 7, 1456–1468 (2000). https://doi.org/10.1038/sj.cgt.7700250

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