Cellular delivery of a replication-conditional herpes simplex virus type 1 (HSV-1) vector provides a means for gene therapy of invasive
tumor cells. LacZ-bearing neural precursor cells, which can migrate and differentiate in the brain, were infected with a
ribonucleotide reductase-deficient HSV-1 mutant virus (rRp450) that replicates only in dividing cells. Replication of rRp450 in neural precursor cells was blocked prior to implantation into the
tumor by growth arrest in late G1 phase through treatment with
mimosine. Viral titers in the medium of
mimosine-treated, rRp450-infected neural precursor cells were below detection levels 3 days after
infection. In culture, after removal of
mimosine and passaging, cells resumed growth and replication of rRp450 so that, 7 days later, virus was present in the medium and cell death was evident.
Mimosine-treated neural precursor cells injected into established intracerebral CNS-1
gliomas in nude mice migrated extensively throughout the
tumor and into the surrounding parenchyma beyond the
tumor over 3 days.
Mimosine-treated neural precursor cells, infected with rRp450 and injected into intracerebral CNS-1
tumors, also migrated within the
tumor with the appearance of foci of HSV-
thymidine kinase-positive (TK+) cells, presumably including
tumor cells, distributed throughout the
tumor and in the surrounding parenchyma over a similar period. This migratory cell delivery method has the potential to expand the range of delivery of HSV-1 vectors to
tumor cells in the brain.