title: Therapy of a murine model of pediatric brain tumors using a herpes simplex virus type-1 ICP34.5 mutant and demonstration of viral replication within the CNS.
abstract: To develop improved therapies for medulloblastoma, we studied the ability of a neuroattenuated HSV-1 ICP34.5 mutant (variant-1716) to replicate within and destory an authentic medulloblastoma cell line known as Med 283 (D283) using immunohistochemistry, in situ hybridization, and viral titrations. In vitro studies showed that variant-1716 replicates in and destroys monolayers of D283 cells with kinetics similar to wild-type strain 17+. When D283 tumor-bearing animals were treated with variant-1716 injected directly into the tumor, there was a statistically significant increase in survival (p < .02) compared to mock-treated tumor-bearing mice. Additionally, several novel observations emerged from this study. Most importantly, we demonstrated focal acute viral replication within murine brain cells, a finding not previously reported with HSV-1 ICP-34.5 variants. Further, the brains of tumor-bearing animals treated with variant-1716 demonstrated persistent viral replication within tumors for several weeks. Thus, we conclude that variant-1716 causes a statistically significant increase in survival of experimental medulloblastomas, but further analysis of the replication of HSV-1 ICP34.5 mutants within the mammalian CNS is necessary to assess its potential long-term toxicity.
authors.affiliation: Division of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Lasner
authors.forename: S
authors.initials: S
authors.lastname: Kesari
authors.forename: S M
authors.initials: SM
authors.lastname: Brown
authors.forename: V M
authors.initials: VM
authors.lastname: Lee
authors.forename: N W
authors.initials: NW
authors.lastname: Fraser
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000818:Animals; D002460:Cell Line; D002528:Cerebellar Neoplasms / Q000628:therapy*; D006224:Cricetinae; D003673:Defective Viruses / Q000235:genetics / Q000502:physiology*; D005260:Female; D015552:Injections, Intralesional; D008527:Medulloblastoma / Q000628:therapy*; D008647:Mesocricetus; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018139:Simplexvirus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D014183:Transplantation, Heterologous; D014764:Viral Proteins / Q000235:genetics*; D014774:Virulence; D014776:Virus Cultivation; D014779:Virus Replication
chemical_list: D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1