Current treatment for brain tumors, such as medulloblastoma, includes aggressive surgical resection, post-operative craniospinal radiation therapy and often, chemotherapy. Treatment-related sequelae range from mild neurologic deficits to neurologic morbidity and death of the patient. Improved treatment regimens are urgently needed. Emerging technologies in which foreign genes are delivered to cells in vivo via retroviruses offer potential new treatments for brain tumors. Since retroviruses effectively infect only dividing cells, it is possible to target cytotoxic genes to brain tumor cells without destroying adjacent post-mitotic nervous tissue. To assess the feasibility of this approach, we plan to prepare two classes of recombinant retroviral vectors containing genes lethal to cells. We will first test the cytopathic effects of these recombinant retroviruses in cultured human medulloblastoma tumor cells and second, test their efficacy in human medulloblastoma tumors in nude mice. One vector will contain a Herpes Simplex Virus thymidine kinase (HSVtk) gene; expression of the tk gene will render the infected cell sensitive to killing by the anti-herpetic drug gancyclovir. Systemic delivery of gancyclovir does not have adverse effects on normal cells. A second vector will contain a disrupter of the cytoskeleton, particularly of the intermediate filament (IF) component. Expression of IF disrupting genes is lethal to cells and does not require administration of exogenous drug. To selectively regulate expression of the lethal gene, cell type-specific promoters derived from genes normally expressed in medulloblastomas will be used to drive expression of the tk or IF-disrupting genes. Expression of lethal genes that are stereotaxically-delivered to brain tumors in vivo offers the potential to selectively destroy rapidly dividing tumor cells without affecting the survival of the surrounding normal brain tissue.
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