1. ¹Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
2. ²Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
3. ³Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
4. ⁴Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA
5. ⁵Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
6. ⁶Brain Tumor Research Laboratories, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: Dr JM Markert, Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, 1050 Faculty Office Towers, 1530 3rd Avenue South, Birmingham, AL 35294-3410, USA. E-mail: markert@uab.edu

Received 1 February 2006; Revised 10 May 2006; Accepted 14 May 2006; Published online 22 September 2006.

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, |[gamma]|₁34.5-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 |[gamma]|₁34.5 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|[sol]|J mice demonstrated lack of neurotoxicity at doses similar to G207, a |[gamma]|₁34.5-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.