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Engineered herpes simplex virus expressing bacterial cytosine deaminase for experimental therapy of brain tumors

Cancer Gene Therapy volume 14, pages 45–56 (2007)Cite this article

Abstract

Lack of effective therapy of primary brain tumors has promoted the development of novel experimental approaches utilizing oncolytic viruses combined with gene therapy. Towards this end, we have assessed a conditionally replication-competent, γ134.5-deleted herpes simplex virus type 1 (HSV-1) expressing cytosine deaminase (CD) for treatment of malignant brain tumors. Our results are summarized as follows: (i) a recombinant HSV (M012) was constructed in which both copies of the γ134.5 gene were replaced with the bacterial CD gene, under the control of the cellular promoter Egr-1; (ii) M012-infected cells in vitro efficiently convert 5-fluorocytosine (5-FC) to 5-fluorouracil, thereby enhancing cytotoxicity of neighboring, uninfected cells; (iii) both direct and bystander cytotoxicity of murine neuroblastoma and human glioma cell lines after infection with M012 were demonstrated; (iv) direct intracerebral inoculation of A/J mice demonstrated lack of neurotoxicity at doses similar to G207, a γ134.5-deleted HSV with demonstrated safety in human patient trials and (v) intratumoral injection of M012 into Neuro-2a flank tumors in combination with 5-FC administration significantly reduced tumor growth versus tumors treated with R3659 combined with 5-FC, or treated with M012 alone. Thus, M012 is a promising new oncolytic HSV vector with an enhanced prodrug-mediated, antineoplastic effect that is safe for intracranial administration.

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Acknowledgements

We thank Bernard Roizman, University of Chicago, for the parent virus R3659 and for many useful discussions. We also thank Cammy Love, Karen Mardis, Kathleen Price, Huey Nguyen and Suman Bharara for technical assistance. Studies performed by the authors were initiated and supported in part by NCI P01 CA 71933 (RJW), and the NINDS Mentored Clinical Scientist Development Award (1K08NSO1942) (JMM). Studies by MBG were initiated and supported in part by an NIH-sponsored Summer Research Fellowship Program (NHLBI T35 HL07473).

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Authors and Affiliations

  1. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    M B Guffey, J N Parker, W S Luckett Jr & R J Whitley

  2. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    M B Guffey & R J Whitley

  3. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA

    G Y Gillespie & J M Markert

  4. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA

    S Meleth

  5. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA

    R J Whitley

  6. Brain Tumor Research Laboratories, University of Alabama at Birmingham, Birmingham, AL, USA

    G Y Gillespie

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  1. M B Guffey
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Correspondence to J M Markert.

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Guffey, M., Parker, J., Luckett, W. et al. Engineered herpes simplex virus expressing bacterial cytosine deaminase for experimental therapy of brain tumors. Cancer Gene Ther 14, 45–56 (2007). https://doi.org/10.1038/sj.cgt.7700978

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