Regression of experimental brain tumors with 6-thioxanthine and Escherichia coli pgt gene therapy

Yasuhiro Ono, Keiro Ikeda, Ming X. Wei, Griffith R. Harsh IV, Takashi Tamiya, E. Antonio Chiocca

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The identification of transgenes with antitumor activity is critical to the development of gene therapy of cancer. Retrovirus-mediated transfer of the Escherichia coli gpt gene into rat C6 glioma cells without subsequent selection still inhibited the proliferation of this mixed polyclonal population upon addition of the prodrug, 6-thioxanthine, with an ID50 of 4.1 μM, whereas parental C6 cells were not affected at a concentration of 500 μM. In a time-course assay, effects of the prodrug on the mixed polyclonal cell proliferation required at least 10 days of exposure. In mixed co-cultures, a bystander effect was not present over the first 4 days of prodrug exposure, but required trypsinization of the co-cultures and replating at lower densities. This 'modified' bystander assay thus revealed a 50% decrease in C6 cell proliferation, even when the initial ratio of gpt-expressing to parental C6 cells was as low as 1:19. In a nude mouse model of subcutaneous tumors, co-grafts of C6 glioma and gpt-retrovirus producer cells displayed retarded growth upon exposure to 6-thioxanthine (6-TX), In a nude mouse model of intracerebral tumors, grafting of the gpf-retrovirus producer cells leads to an 80% reduction in intracerebral tumor volumes after 6-TX treatment. This reduction results in a 28% increase in the mean time of survival of animals that harbor intracerebral tumors (p < 0.0005). These antitumor effects indicate that the gpt/6-TX enzyme/prodrug pair is a promising alternative to the thymidine kinase gene and ganciclovir combination in the gene therapy of cancer.

Original languageEnglish (US)
Pages (from-to)2043-2055
Number of pages13
JournalHuman Gene Therapy
Volume8
Issue number17
DOIs
StatePublished - Nov 20 1997
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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