Skip to main content
SpringerLink
Log in

5-Fluorocytosine-mediated apoptosis and DNA damage in glioma cells engineered to express cytosine deaminase and their enhancement with interferon

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

To explore the antitumor mechanism of bacterial cytosine deaminase plus 5-fluorocytosine (CD/5-FCyt) in combination with interferons (IFNs), glioma cells were transduced with recombinant retroviruses expressing CD. The transduced glioma cells become sensitive to the nontoxic prodrug 5-FCyt. Apoptosis, DNA damage, bystander effect, and inhibition of thymidylate synthase (TS) and DNA synthesis are associated with CD/5-FCyt-mediated glioma cell killing. Furthermore, IFNs enhance this effect by increasing DNA damage and further inhibiting TS activity. The bystander effect is mediated by the release of cytotoxic metabolites of 5-FCyt into the extracellular milieu triggering apoptosis and DNA damage. Our data indicate that the use of CD/5-FCyt in combination with IFNs may provide a more effective approach for the treatment of brain tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Takamiya Y, Short MP, Moolten FL, Fleet C, Mineta T, Breakefield XO, Martuza RL: An experimental model of retrovirus gene therapy for malignant brain tumors. J Neurosurg 79: 104–110, 1993

    Google Scholar 

  2. Ram Z, Culver KW, Walbridge S, Blaese RM, Oldfield EH: In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res 53: 83–88, 1993

    Google Scholar 

  3. Boviatsis EJ, Chase M, Wei MX, Tamiya T, Hurford RK Jr, Kowall NW, Tepper RI, Breakefield XO, Chiocca EA: Gene transfer into experimental brain tumors mediated by adenovirus, herpes simplex virus, and retrovirus vectors. Hum Gene Therapy 5: 183–191, 1994

    Google Scholar 

  4. Kramm CM, Sena-Esteves M, Barnett FH, Rainov NG, Schuback DE, Yu JS, Pechan PA, Paulus W, Chiocca EA, Breakefield XO: Gene therapy for brain tumors. Br Pathol 5: 345–381, 1995

    Google Scholar 

  5. Mullen CA, Kilstrup M, Blaese RM: Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5′-fluorocytosine: a negative selection system. Proc Natl Acad Sci USA 89: 33–37, 1992

    Google Scholar 

  6. Consalvo M, Mullen CA, Modesti A, Musiani P, Allione A, Cavallo F, Giovarelli M, Forni G: 5-fluorocytosine-induced eradiction of murine adenocarcinomas engineered to express the cytosine deaminase suicide gene requires host immune competence and leaves an efficient memory. J Immunol 154: 5302–5312, 1995

    Google Scholar 

  7. Huber BE, Austin EA, Good SS, Knick VC, Tibbels S, Richards CA: In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase. Cancer Res 53: 4619–4626, 1993

    Google Scholar 

  8. Harris JD, Gutierrez AA, Hurst HC, Sikora K, Lemoine NR: Gene therapy for cancer using tumor-specific prodrug activation. Gene Therapy 1: 170–175, 1994

    Google Scholar 

  9. Huber BE, Austin EA, Richards CA, Davis ST, Good SS: Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA 91: 8302–8306, 1994

    Google Scholar 

  10. Hirschowitz EA, Ohwada A, Pascal WR, Russi TJ, Crystal RG: In vivo adenovirus-mediated gene transfer of the Escherichia coli cytosine deaminase gene to human colon carcinoma-derived tumors induces chemosensitivity to 5-fluorocytosine. Hum Gene Therapy 6: 1055–1063, 1995

    Google Scholar 

  11. Kreuser ED, Wadler S, Thiel E: Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Recent Results in Cancer Research 139: 371–382, 1995

    Google Scholar 

  12. Mullen CA, Coale MM, Lowe R, Blaese RM: Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor. Cancer Res 54: 1503–1506, 1994

    Google Scholar 

  13. Pazdur R, Bready B, Moore DF Jr: Clinical trials of fluorouracil with α-interferon in advanced colorectal carcinomas. Seminars in Oncology 18: 67–70, 1991

    Google Scholar 

  14. Kirkwood JM: Studies of interferons in the therapy of melanoma. Seminars in Oncology 18: 83–90, 1991

    Google Scholar 

  15. Meadows LM, Walther P, Ozer H: α-Interferon and 5-fluorouracil: possible mechanisms of antitumor action. Seminars in Oncology 18: 71–76, 1991

    Google Scholar 

  16. Hoff DDV: In vitro data supporting interferon plus cytotoxic agent combinations. Seminars in Oncology 18: 58–61, 1991

    Google Scholar 

  17. Neefe JR, John W: Mechanisms of interaction of interferon and 5-fluorouracil in solid tumors. Seminars in Oncology 18: 77–82, 1991

    Google Scholar 

  18. Grem JL, van Groeningen CJ, Ismail AA, Johnston PG, Alexander HR, Allegra CJ: The role of interferon-α as a modulator of fluorouracil and leucovorin. Eur J Cancer 31: 1316–1320, 1995

    Google Scholar 

  19. Spector A, Kleiman NJ, Huang R-RC, Wang RR: Repair of H2O2-induced DNA damage in bovine lens epithelial cell cultures. Exp Eye Res 49: 685–698, 1989

    Google Scholar 

  20. Houghton JA, Morton CL, Adkins DA, Rahman A: Locus of the interaction among 5-fluorouracil, leucovorin, and interferon-αa in colon carcinoma cells. Cancer Res 53: 4243–4250, 1993

    Google Scholar 

  21. Maniatis T, Fritsch EF, Sambrook J: Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. 2nd ed., 1989

    Google Scholar 

  22. Cornetta K, Anderson WF: Protamine sulfate as an effective alternative to polybrene in retroviral-mediated gene transfer: implications for human gene therapy. J Virol Methods 23: 187–194, 1989

    Google Scholar 

  23. Karp JE, Broder S: New directions in molecular medicine. Cancer Res 54: 653–665, 1994

    Google Scholar 

  24. Lowe WL Jr, Meyer T, Karpen CW, Lorentzen LR: Regulation of insulin-like growth factor I production in rat C6 glioma cells: possible role as an autocrine/paracrine growth factor. Endocrinology 130: 2683–2691, 1992

    Google Scholar 

  25. Yalowich JC, Kalman TI: Rapid determination of thymidylate synthase activity and its inhibition in intact L1210 leukemia cells in vitro.Biochem Pharmacol 34: 2319–2324, 1985

    Google Scholar 

  26. Vile R, Russell SJ: Gene transfer technologies for the gene therapy of cancer. Gene Therapy 1: 88–98, 1994

    Google Scholar 

  27. Colombo BM, Benedetti S, Ottolenghi S, Mora M, Pollo B, Poli G, Finocchiaro G: The ‘bystander effect’: association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice. Hum Gene Therapy 6: 763–772, 1995

    Google Scholar 

  28. Yin MB, Rustum YM: Comparative DNA strand breakage induced by FUra and FdUrd in human ileocecal adenocarcinoma (HCT-8) cells: relevance to cell growth inhibition. Cancer Commun 3: 45–51, 1991

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, New York University School of Medicine, New York, USA

    Zhao-Hui Wang, Stanley Samuels, Miguel A. Gama Sosa & Edwin H. Kolodny

Authors
  1. Zhao-Hui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stanley Samuels
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miguel A. Gama Sosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edwin H. Kolodny
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, ZH., Samuels, S., Sosa, M.A.G. et al. 5-Fluorocytosine-mediated apoptosis and DNA damage in glioma cells engineered to express cytosine deaminase and their enhancement with interferon. J Neurooncol 36, 219–229 (1998). https://doi.org/10.1023/A:1005883128175

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005883128175

Search

Navigation