Herpes Simplex Virus Thymidine Kinase Gene Therapy for Rat Malignant Brain Tumors

Abstract

Transfer of a herpes simplex virus-derived thymidine kinase (HSV-tk) gene into brain tumor cells and subsequent ganciclovir (GCV) treatment has been shown by others to be an effective treatment in rats with intracerebrally inoculated 9L gliosarcomas. Mechanism of action and reproducibility are, however, still a matter of debate. We have used the same model to test the therapeutic effects of both retrovirus- and adenovirus-mediated transfer of the HSV-tk gene followed by GCV treatment. Survival time of rats with intracerebral 9L tumors was significantly prolonged after a single administration of adenovirus carrying a HSV-tk gene as compared to controls. Retrovirus-mediated gene transfer also resulted in significantly prolonged survival time when recombinant retrovirus-producing cells were transplanted. Direct injection of the recombinant retrovirus, HSV-tk-expressing cells, virus-producing cells without GCV administration and recombinant retrovirus-lacZ or interleukin-2 (IL-2)-producing cells did not result in tumor cell kill. In the present study, no significant difference in survival of 9L brain tumor carrying rats was found after treatment with adenovirus as compared to retrovirus-mediated HSV-tk-mediated gene transfer and subsequent GCV treatment.

Overview summary

Transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) treatment leads to specific killing of dividing cells. Brain tumors are embedded in nondividing tissue and are, therefore, good candidates for this therapeutic approach. We demonstrate that the 9L rat gliosarcoma and U251 human glioma cells can be efficiently transduced by adenoviral vectors using lacZ as a marker gene. Consequently we treated rats with an intracerebral graft of 9L tumor cells with adenoviral vectors carrying HSV-tk or in a parallel experiment with a retrovirus producer cell line-shedding retrovirus vectors carrying HSV-tk followed by GCV administration. Both groups survived significantly longer than the controls.