Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine

Hum Gene Ther. 2000 Jan 1;11(1):77-89. doi: 10.1089/10430340050016175.

Abstract

Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared with cells transduced with CD alone. In a rat brain tumor model, decreased amounts of CD and UPRT vectors were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect as detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD + UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Brain Neoplasms / therapy*
  • Cytosine Deaminase
  • Flucytosine / therapeutic use*
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Genetic Vectors / adverse effects
  • Magnetic Resonance Imaging
  • Nucleoside Deaminases / genetics*
  • Pentosyltransferases / genetics*
  • Rats
  • Recombination, Genetic
  • Tumor Cells, Cultured

Substances

  • Flucytosine
  • Pentosyltransferases
  • uracil phosphoribosyltransferase
  • Nucleoside Deaminases
  • Cytosine Deaminase