Cytosine deaminase/5-fluorocytosine-based vaccination against liver tumors: evidence of distant bystander effect

J Natl Cancer Inst. 1999 Dec 1;91(23):2014-9. doi: 10.1093/jnci/91.23.2014.


Background: The cytosine deaminase gene of Escherichia coli converts the nontoxic compound 5-fluorocytosine into 5-fluorouracil (5-FU), thereby acting as a suicide gene when introduced into cancer cells, killing the cells when they are exposed to 5-fluorocytosine. We analyzed the efficacy of using cytosine deaminase-bearing cancer cells as an autologous tumor vaccine in a rat model that mimics liver metastasis from colon carcinoma.

Methods: We introduced a plasmid vector containing the E. coli cytosine deaminase gene into a BDIX rat colon carcinoma cell line. Intrahepatic injection of the modified cells in syngeneic animals generates a single experimental liver "suicide tumor." We then analyzed the effect of 5-fluorocytosine treatment in terms of regression of cytosine deaminase-expressing cells in vivo as well as protection against wild-type cancer cells.

Results: Treatment with 5-fluorocytosine induced regression of cytosine deaminase-expressing (CD+) tumors, with seven of 11 treated animals being tumor free at the end of 30 days and a statistically significant difference in tumor volumes between treated and control animals (two-sided P<.0001). Intrahepatic injection of CD+ cells followed by 5-fluorocytosine treatment rendered the treated animals resistant to challenge with wild-type tumor cells, with no (zero of seven) treated animals developing wild-type tumors in contrast to all (four of four) control animals. Moreover, in animals with established wild-type liver tumors, injection of CD+ tumor cells followed by 5-fluorocytosine treatment produced a statistically significant increase in survival time (two-sided P<.0001). In vivo immunodepletion and immunohistologic analysis of experimental tumors indicate that natural killer cells are the major immune component involved in this antitumor effect.

Conclusions and implications: Taken together, these results suggest the potential use of suicide gene-modified tumor cells as therapeutic vaccines against liver metastasis from colon carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology*
  • Antimetabolites / pharmacology*
  • Antineoplastic Agents
  • Cancer Vaccines* / pharmacology
  • Colonic Neoplasms / pathology
  • Cytosine Deaminase
  • Escherichia coli / enzymology
  • Flow Cytometry
  • Flucytosine / pharmacology*
  • Fluorouracil
  • Genetic Therapy*
  • Killer Cells, Natural
  • Liver Neoplasms / immunology
  • Liver Neoplasms / secondary
  • Liver Neoplasms / therapy*
  • Male
  • Nucleoside Deaminases / genetics*
  • Rats
  • Transfection
  • Tumor Cells, Cultured


  • Antifungal Agents
  • Antimetabolites
  • Antineoplastic Agents
  • Cancer Vaccines
  • Flucytosine
  • Nucleoside Deaminases
  • Cytosine Deaminase
  • Fluorouracil