Among the appealing features of adenoviruses as vectors for transfer of genes into the central nervous system (CNS) are that they are not neurotoxic, they can accommodate the insertion of several large genes, they are not associated with the hazards of insertional mutagenesis, and they can be concentrated to a high-titer preparation. The authors evaluated the feasibility of using adenovirally mediated gene transfer into cultured human
glioma cells and in rat models of solid
brain tumors and
meningeal cancer. Replication-deficient adenoviral vector particles carrying a nuclear-localizing lacZ gene were injected into established 9L cerebral
gliomas in Fischer rats. In addition, the adenoviral vector was injected into the subarachnoid space, either simultaneously with intrathecal
tumor inoculation or after establishing leptomeningeal
cancer. The brains and spinal cords were removed at various intervals for histochemical evaluation for
beta-galactosidase activity using
X-Gal staining. Additional rats received a stereotactic intracerebral injection of the vector into normal brain. No clinical abnormalities were observed in the injected rats. Injection of the adenoviral vector into normal brain resulted in diffuse transduction of astrocytes, microglia, neurons, and endothelial cells at the injection site. Injection of a high-concentration vector preparation into cerebral
gliomas resulted in effective
tumor transduction.
Intrathecal injection of the vector in rats with
meningeal cancer resulted in transduction of the infiltrating
tumor in the subarachnoid space when
injections were given simultaneously with, or 7 days after,
tumor inoculation. Transduction rates of both solid and leptomeningeal
tumors correlated with the number of injected particles. These results suggest that adenoviral vectors can efficiently transduce solid
brain tumors and that the vectors survive in the cerebrospinal fluid for a sufficient period of time to allow leptomeningeal
tumor transduction. Adenoviral vector should be evaluated for its potential use in therapeutic gene transfer approaches in
malignancies of the CNS.