Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: A gene-marking and neuropathological study

Griffith R. Harsh, Thomas S. Deisboeck, David N. Louis, John Hilton, Michael Colvin, Jonathan S. Silver, Nazer H. Qureshi, Jean Kracher, Diane Finkelstein, Ennino A. Chiocca, Fred H. Hochberg

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Object. The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors beating the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens. Methods. Five patients with malignant recurrent gliomas underwent stereotactic biopsy sampling and intratumoral implantation procedures with three aliquots of 106 vector-producing cells (VPCs) in columns. After 5 days, the tumor was resected and the tumor bed reimplanted with VPCs, and a course of GCV was given. Patients received clinical and radiological follow up for 6 months. Tumor specimens were analyzed neuropathologically and for tk gene expression by anti-TK immunohistochemistry and TK enzymatic activity. Four patients tolerated the treatment well but experienced tumor progression. The other developed an abscess after the second operation and died. Increased TK enzymatic activity was demonstrated in the one tumor specimen analyzed. Immunohistochemical evidence of tk gene expression was limited to VPCs. Transduction of tumor cells was not seen. Viable tumor cells were seen near VPCs containing TK. The lymphocytic immune response was mild. Conclusions. Except for the risk of infection inherent in reoperation, this tk-GCV paradigm was both feasible and safe. Pathological studies indicated that limited dissemination of VPCs and vector from the infusion site and failure to transduce tumor cells with the tk gene are major barriers to efficacy.

Original languageEnglish (US)
Pages (from-to)804-811
Number of pages8
JournalJournal of Neurosurgery
Volume92
Issue number5
DOIs
StatePublished - May 2000
Externally publishedYes

Keywords

  • Brain neoplasm
  • Ganciclovir
  • Gene therapy
  • Glioblastoma multiforme

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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