Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity (original) (raw)

Cancer Gene Therapy volume 7, pages 637–643 (2000)Cite this article

Abstract

Uracil phosphoribosyltransferase (UPRT) of Escherichia coli origin can convert 5-fluorouracil (5-FU), a chemotherapeutic agent widely used for solid tumors, to an active intermediate, 5-fluorouridine-5′-monophosphate, as mammalian orotate phosphoribosyltransferase does. To examine whether the E. coli UPRT gene expressed in tumor cells can confer increased sensitivity to 5-FU, we retrovirally transduced Colon 26 cells, a murine colon carcinoma cell line, with the UPRT gene (Colon 26/UPRT cells) and tested the in vivo antitumoral effect of 5-FU in syngeneic immunocompetent mice. After 5-FU administration, tumors of Colon 26/UPRT cells regressed, whereas those of wild-type cells were unaffected. The mice that once eliminated Colon 26/UPRT tumors after 5-FU treatment rejected wild-type cells that were subsequently inoculated but not irrelevant syngeneic tumor cells. This suicide gene/prodrug system was less efficient in nude mice, suggesting that mature αβ T cells play a role in the antitumoral effect. The cytotoxicity mediated by the bystander effect was marginal in this system, contrary to the herpes simplex virus-thymidine kinase gene/ganciclovir system. Therefore, expression of the UPRT gene in tumor cells followed by 5-FU administration is a possible strategy for cancer gene therapy, but potentiation of the bystander effect is required for its therapeutic application.

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Authors and Affiliations

  1. Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan
    Kiyoko Kawamura, Kentaro Tasaki & Masastoshi Tagawa
  2. Department of Surgery (II), Chiba University School of Medicine, Chiba, Japan
    Kentaro Tasaki
  3. Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Cancer Institute, Tokyo, Japan
    Hirofumi Hamada
  4. Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan
    Hirofumi Hamada
  5. Division of Chemotherapy, Chiba Cancer Center Research Institute, Chiba, Japan
    Keizo Takenaga
  6. Chiba Cancer Center Research Institute, Chiba, Japan
    Shigeru Sakiyama

Authors

  1. Kiyoko Kawamura
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  2. Kentaro Tasaki
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  3. Hirofumi Hamada
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  4. Keizo Takenaga
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  5. Shigeru Sakiyama
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  6. Masastoshi Tagawa
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Corresponding author

Correspondence toMasastoshi Tagawa.

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Kawamura, K., Tasaki, K., Hamada, H. et al. Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity.Cancer Gene Ther 7, 637–643 (2000). https://doi.org/10.1038/sj.cgt.7700154

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