Evaluation of genetically engineered herpes simplex viruses as oncolytic agents for human malignant brain tumors

Academic Article

Abstract

  • Earlier studies have shown that genetically engineered herpes simplex viruses (e.g., HSV-1) are effective in killing malignant tumor cells both in vitro and in various murine tumor models. This report focuses on a panel of five genetically engineered vital mutants of the γ 34.5 gene, which was shown previously to cause reduction in viral replication and associated neurovirulence of HSV. These include R3616, which has both copies of γ 34.5 deleted, R4009, which has a stop codon inserted after codon 28 in both copies of the γ 34.5 gene, R849, which contains a lacZ gene inserted in place of the γ 34.5, R908, which lacks 41 codons in frame after codon 72 of the γ 34.5, and R939, which carries a stop codon precluding the translation of the COOH-terminal domain of the γ 34.5 gene. We report the following: (a) all five mutant HSVs were avirulent in experimental animals but were cytotoxic for human tumor cells in vitro and in vivo; (b) the γ 34.5 HSV replicated in human glioma cells almost as efficiently as wild-type HSV-1(F) based on replication assays, in situ hybridization for viral DNA, and expression of infected cell protein 27; (c) capacity of mutant HSVs to kill human cells derived from glioblastoma multiforme (CH-235MG, D-37MG, D-54MG, D-65MG, U-251MG, U-373MG, and NK-MG-1), anaplastic astrocytoma (Hs-683), anaplastic glioma (U-87MG and U-138MG), gliosarcoma (D-32GS), or normal human astrocytes demonstrated that glioma cells varied in their susceptibility to HSV-mediated cytotoxicity and that cultured astrocytes were two to three orders of magnitude less susceptible to killing than were malignant glia; and (d) scid mice, which received 0.5 or 5 x 10 plaque-forming units of R4009, either were coinoculated at the time of intracranial transplantation with 10 U251MG or D-54MG human glioma cells or received the cells intratumorally 5 days after tumor induction and experienced significant increases in median survivals, with no histopathological indication of an infectious encephalitic process. Genetically engineered γ 34.5 HSV mutants appear to be a potentially safe biotherapeutic agent for experimental treatment of uniformly fatal malignant brain tumors. 1 1 1 1 1 1 1 1 - 6 6 -
  • Published In

  • Cancer Research  Journal
  • Author List

  • Andreansky S; Soroceanu L; Flotte ER; Chou J; Markert JM; Gillespie GY; Roizman B; Whitley RJ
  • Start Page

  • 1502
  • End Page

  • 1509
  • Volume

  • 57