Bystander effect caused by cytosine deaminase gene and 5-fluorocytosine in vitro is substantially mediated by generated 5-fluorouracil

Anticancer Res. Sep-Oct 1998;18(5A):3399-406.


Because it appears impossible to transfer toxic genes to all the cells of a cancer, the bystander effect is critical to induce effective antitumor effects. In the present study, possible in vitro mechanisms of the bystander effect by the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) were investigated. CD-transduced cancer cells exhibited much higher sensitivity to 5-FC compared to parental cells. CD-transduced cells caused killing of neighboring parental cells in the presence of 5-FC, irrespective of direct cell-to-cell contact. Media conditioned by CD-transduced cells and 5-FC contained considerable amounts of 5-fluorouracil (5-FU) and exhibited profound cytotoxicity on parental cells. Furthermore, this killing ability of conditioned media correlated well with 5-FU levels converted from 5-FC by CD-transduced cells. CD was shown not to be secreted into media from cells. These results indicate that diffusible 5-FU plays the substantially causative role in the in vitro bystander effect caused by the CD/5-FC system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / metabolism
  • Antimetabolites, Antineoplastic / pharmacology*
  • Culture Media, Conditioned / pharmacology
  • Cytosine Deaminase
  • Flucytosine / metabolism
  • Flucytosine / pharmacology*
  • Fluorouracil / metabolism
  • Fluorouracil / pharmacology*
  • Mice
  • Nucleoside Deaminases / genetics*
  • Nucleoside Deaminases / metabolism
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*
  • Rats
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism


  • Antimetabolites, Antineoplastic
  • Culture Media, Conditioned
  • Prodrugs
  • Flucytosine
  • Nucleoside Deaminases
  • Cytosine Deaminase
  • Fluorouracil