1. ¹Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
2. ²Center for Applied Cancer Science, Belfer Institute for Innovative Cancer Science, Departments of Medical Oncology, Medicine and Genetics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
3. ³Dardinger Laboratory for Neuro-Oncology and Neurosciences, Department of Neurosurgery, James Comprehensive Cancer Center and The Ohio State University Medical Center, Columbus, OH, USA

Correspondence: Dr EA Chiocca, Department of Neurosurgery, The Ohio State University, Wiseman Hall, 400 West 10th Avenue, Columbus, OH 43210, USA. E-mail: EA.Chiocca@osumc.edu

Received 5 July 2007; Revised 14 January 2008; Accepted 8 February 2008; Published online 17 March 2008.

Abstract

Oncolytic herpes simplex viruses (HSVs), in clinical trials for the treatment of malignant gliomas, are assumed to be selective for tumor cells because their replication is strongly attenuated in quiescent cells, but not in cycling cells. Oncolytic selectivity is thought to occur because mutations in viral ICP6 (encoding a viral ribonucleotide reductase function) and/or 34.5 function are respectively complemented by mammalian ribonucleotide reductase and GADD34, whose genes are expressed in cycling cells. However, it is estimated that only 5–15% of malignant glioma cells are in mitosis at any one time. Therefore, effective replication of HSV oncolytic viruses might be limited to a subpopulation of tumor cells, since at any one time the majority of tumor cells would not be cycling. However, we report that an HSV with defective ICP6 function replicates in quiescent cultured murine embryonic fibroblasts obtained from mice with homozygous p16 deletions. Furthermore, intracranial inoculation of this virus into the brains of p16-/- mice provides evidence of viral replication that does not occur when the virus is injected into the brains of wild-type mice. These approaches provide in vitro and in vivo evidence that ICP6-negative HSVs are 'molecularly targeted,' because they replicate in quiescent tumor cells carrying specific oncogene deletions, independent of cell cycle status.