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  • Acquired Diseases
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HSV vector cytotoxicity is inversely correlated with effective TK/GCV suicide gene therapy of rat gliosarcoma

Gene Therapy volume 7, pages 1483–1490 (2000)Cite this article

Abstract

Herpes simplex virus (HSV)-mediated delivery of the HSV thymidine kinase (tk) gene to tumor cells in combination with ganciclovir (GCV) administration may provide an effective suicide gene therapy for destruction of malignant glioblastomas. However, because HSV is a highly cytotoxic agent, gene expression from the virus is short-lived which may limit the effectiveness of HSVtk/GCV therapy. Using different replication-defective HSVtk gene vectors, we compared HSV vector backgrounds for their cytotoxic activity on infection of 9L gliosarcoma cells in culture and brain tumors in rats and evaluated the impact of vector toxicity on the effectiveness of tk/GCV-mediated suicide gene therapy. As reported previously for other cell lines, a vector deleted for both copies of the immediate–early (IE) gene ICP4 (SOZ.1) was highly toxic for 9L cells in culture while a vector deleted in addition for the ICP22 and ICP27 IE genes (T.1) reduced or arrested 9L cell proliferation with more limited cell killing. Nevertheless, both vectors supported widespread killing of uninfected cells in the presence of GCV following low multiplicity infections, indicating that vector cytotoxicity did not preempt the production of vector-encoded TK enzyme necessary for the killing of uninfected cells by the HSV-tk/GCV bystander effect. Although an SOZ.1-related vector (SHZ.2) caused tumor cell necrosis in vivo, injection of SHZ.2 at multiple coordinates thoughout the tumor followed by GCV administration failed to prolong markedly the survival of tumor- bearing rats. In contrast, a single injection of T.1 produced a life-extending response to GCV. These results indicate that vector cytotoxicity can limit the efficacy of HSV-tk/GCV treatment in vivo, which may be due to premature termination of tk gene expression with attendant abortion of the bystander effect.

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Acknowledgements

We wish to thank Kate Sullivan of the Department of Molecular Genetics and Biochemistry for technical assistance. This work was supported by NIH Grants GM34534 and AR44526 to JCG.

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  1. P C Marconi

    Present address: Department of Experimental and Diagnostic Medicine (Section of Microbiology) and Biotechnology Center, University of Ferrara, Ferrara, Italy

Authors and Affiliations

  1. Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    S Moriuchi, D M Krisky, P C Marconi, M Tamura, J B Cohen & J C Glorioso

  2. Department of Neurosurgery, Osaka University Medical School Osaka, Japan

    S Moriuchi, K Shimizu & T Yoshimine

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  1. S Moriuchi
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Moriuchi, S., Krisky, D., Marconi, P. et al. HSV vector cytotoxicity is inversely correlated with effective TK/GCV suicide gene therapy of rat gliosarcoma. Gene Ther 7, 1483–1490 (2000). https://doi.org/10.1038/sj.gt.3301265

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