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The Journal of Neuroscience, February 20, 2008, 28(8):1882-1893; doi:10.1523/JNEUROSCI.4905-07.2008

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Neurobiology of Disease
Systemic Vesicular Stomatitis Virus Selectively Destroys Multifocal Glioma and Metastatic Carcinoma in Brain

Koray Özduman, Guido Wollmann, Joseph M. Piepmeier, and Anthony N. van den Pol

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520

Correspondence should be addressed to Anthony N. van den Pol, Department of Neurosurgery, Yale University, School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: anthony.vandenpol{at}yale.edu

Metastatic tumors and malignant gliomas make up the majority of cancers in the brain. They are invariably fatal and there is currently no cure. From in vitro comparisons of a number of viruses, we selected one that appeared the best in selectively killing glioblastoma cells. This replication-competent virus, the glioma-adapted vesicular stomatis virus strain VSVrp30a, was used for in vivo tests with the underlying view that infection of tumor cells will lead to an increase in the number of viruses subsequently released to kill additional tumor cells. Intravenous injection of VSVrp30a expressing a green fluorescent protein reporter, rapidly targeted and destroyed multiple types of human and mouse tumors implanted in the mouse brain, including glioblastoma and mammary tumors. When tumors were implanted both in the brain and peripherally, emulating systemic cancer metastasis, tumors inside and outside the brain were simultaneously infected. Intranasal inoculation, leading to olfactory nerve transport of the virus into the brain, selectively infected and killed olfactory bulb tumors. Neither control cortical wounds nor transplanted normal mouse or human cells were targeted, indicating viral tumor selectivity. Control viruses, including pseudorabies, adeno-associated, or replication-deficient VSV, did not infect the brain tumor. Confocal laser time-lapse imaging through a cranial window showed that intravenous VSV infects the tumor at multiple sites and kills migrating tumor cells. Disrupted tumor vasculature, suggested by dye leakage, may be the port of entry for intravenously delivered VSV. Quantitative PCR analysis of how VSVrp30a selectively infected tumor cells suggested multiple mechanisms, including cell surface binding and internalization.

Key words: brain cancer; glioma; metastasis; vesicular stomatitis virus; oncolytic virus; fluorescence microscopy

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Received June 14, 2007; revised Jan. 2, 2008; accepted Jan. 3, 2008.

Correspondence should be addressed to Anthony N. van den Pol, Department of Neurosurgery, Yale University, School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: anthony.vandenpol{at}yale.edu

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