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Long-Term Survival of Rats Harboring Brain Neoplasms Treated with Ganciclovir and a Herpes Simplex Virus Vector That Retains an Intact Thymidine Kinase Gene¹

Neurosurgery Service [E. J. B., E. A. C.] and Molecular Neurogenetics Laboratory, Department of Neurology [E. J. B., J. S. P., M. S. E., M. C., C. M. K., M. X. W., X. O. B., E. A. C.] and Biostatistics Unit, Department of Radiation Oncology [J. T. E.], Massachusetts General Hospital, and Program in Neurosciences [X. O. B.], Harvard Medical School, Boston, Massachusetts 02114

Survival of rats harboring cerebral 9L gliosarcomas can be significantly extended by an intratumoral inoculation with a herpes simplex virus vector, designated as hrR3. This vector, which bears the lacZ reporter gene, is defective in the gene encoding ribonucleotide reductase, allowing for replication in dividing tumor cells but not in postmitotic neural cells. It also possesses an intact viral thymidine kinase (TK) gene, which confers chemosensitivity to ganiclovir. In this study, the ability of ganciclovir to potentiate the antitumor effect of hrR3 was evaluated. In culture, there was a 23% decrease in the growth of 9L cells treated with hrR3 plus ganciclovir compared to hrR3 alone (P < 0.01). The combination of hrR3 plus ganciclovir led to the long-term survival of 48% of rats harboring intracerebral 9L gliosarcomas compared to 20% survival in the hrR3 group (P < 0.05). Ganciclovir treatment had no effect on the growth of tumor cells in vitro or in vivo when a herpes simplex virus vector with a defective TK gene was used. Immunocytochemistry confirmed selective expression of the TK gene in cells within the tumor. These findings indicate that the TK gene can potentiate the antitumor effect of the hrR3 herpes simplex virus vector and provide the basis for placing additional therapeutic genes in the genome of hrR3.

¹ This work was supported by grants from the NIH National Institutes of Neurologic Disorders and Stroke NS 24279-08 (to E. A. C. and X. O. B.). E. J. B. is a Fellow of the Alexandros Onassis Foundation. C. M. K. is a fellow of the Deutsche Krebshilfe.

² To whom requests for reprints should be addressed, at Molecular Neurogenetics Laboratory, 6th Floor, Massachusetts General Hospital-East Building, Charlestown, MA 02129.

Received 8/ 5/94. Accepted 10/ 6/94.

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