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Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy

Cancer Gene Therapy volume 14, pages 57–65 (2007)Cite this article

Abstract

A promising approach for cancer gene therapy is the combination of adenovirus vectors (AdV) with the suicide gene cytosine deaminase and uracil phosphoribosyl transferase (CD∷UPRT). While such vectors have been tested in tumor cell lines and xenograft models, it is not clear how these therapeutic vectors would perform in primary human tumors. We, thus, examined the effect of the combination of a recombinant adenovirus expressing the CD∷UPRT (AdCU) with 5-fluorocytosine (5-FC) on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers. In such models, we have found a direct correlation between the patients' response to 5-FU and the response shown by the cancer cells in vitro, confirming the clinical relevance of this methodology. Our findings demonstrated that this combination was able to kill primary tumor cells, including those that had developed resistance to 5-FU. Furthermore, while proliferating cells were more susceptible to 5-FU, the combination was effective in both rapid and slow proliferating samples. Our study demonstrated that this gene therapy approach could provide an effective therapeutic option for cancers and is not affected by acquired 5-FU resistance. Also of importance is the effectiveness of this gene therapy approach on slower proliferating cells that is typical of the majority of cancers in vivo. This suggests a greater likelihood that it will be effective in a clinical setting.

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References

  1. Miyagi T, Koshida K, Hori O, Konaka H, Katoh H, Kitagawa Y et al. Gene therapy for prostate cancer using the cytosine deaminase/uracil phosphoribosyltransferase suicide system. J Gene Med 2003; 5: 30–37.

    Article  CAS  PubMed  Google Scholar 

  2. Chung-Faye GA, Chen MJ, Green NK, Burton A, Anderson D, Mautner V et al. In vivo gene therapy for colon cancer using adenovirus-mediated, transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase. Gene Therapy 2001; 8: 1547–1554.

    Article  CAS  PubMed  Google Scholar 

  3. Koyama F, Sawada H, Hirao T, Fujii H, Hamada H, Nakano H . Combined suicide gene therapy for human colon cancer cells using adenovirus-mediated transfer of Escherichia coli cytosine deaminase gene and Escherichia coli uracil phosphoribosyltransferase gene with 5-fluorocytosine. Cancer Gene Ther 2000; 7: 1015–1022.

    Article  CAS  PubMed  Google Scholar 

  4. Yazawa K, Fisher WE, Brunicardi FC . Current Progress in suicide gene therapy for cancer. World J Surg 2002; 26: 783–789.

    Article  PubMed  Google Scholar 

  5. Kirn D, Niculescu-Duvaz I, Hallden G, Springer CJ . The emerging fields of suicide gene therapy and virotherapy. Trends Mol Med 2002; 8: S68–S73.

    Article  CAS  PubMed  Google Scholar 

  6. Ramnaraine M, Pan W, Goblirsch M, Lynch C, Lewis V, Orchard P et al. Direct and bystander killing of sarcomas by novel cytosine deaminase fusion gene. Cancer Res 2003; 63: 6847–6854.

    CAS  PubMed  Google Scholar 

  7. Kawamura K, Bahar R, Namba H, Seimiya M, Takenaga K, Hamada H et al. Bystander effect in uracil phosphoribosyltransferase/5-fluorouracil-mediated suicide gene therapy is correlated with the level of intracellular communication. Int J Oncol 2001; 18: 117–120.

    CAS  PubMed  Google Scholar 

  8. Pope IM, Poston GJ, Kinsella AR . The role of the bystander effect in suicide gene therapy. Eur J Cancer 1997; 33: 1005–1016.

    Article  CAS  PubMed  Google Scholar 

  9. Denny WA . Prodrugs for gene-directed enzyme-prodrug therapy (suicide gene therapy). J Biomed Biotechnol 2003; 2003: 48–70.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bourbeau D, Lavoie G, Nalbantoglu J, Massie B . Suicide gene therapy with an adenovirus expressing the fusion gene CD∷UPRT in human glioblastomas: different sensitivities correlate with p53 status. J Gene Med 2004; 6: 1320–1332.

    Article  CAS  PubMed  Google Scholar 

  11. Nishiyama T, Kawamura Y, Kawamoto K, Matsumuru H, Yamamoto N, Ito T et al. Antineoplastic effects in rats of 5-fluorocytosine in combination with cytosine deaminase capsules. Cancer Res 1985; 45: 1753–1761.

    CAS  PubMed  Google Scholar 

  12. 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 1992; 89: 33–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kanai F, Kawakami T, Hamada H, Sadata A, Yoshida Y, Tanaka T et al. Adenovirus-mediated transduction of Escherichia coli uracil phosphoribosyltransferase gene sensitizes cancer cells to low concentrations of 5-fluorouracil. Cancer Res 1998; 58: 1946–1951.

    CAS  PubMed  Google Scholar 

  14. Tiraby M, Cazaux C, Baron M, Drocourt D, Reynes JP, Tiraby G . Concomitant expression of E. coli cytosine deaminase and uracil phosphoribosyltransferase improves the cytotoxicity of 5-fluorocytosine. FEMS Microbiol Lett 1998; 176: 41–49.

    Article  Google Scholar 

  15. Grem JL . 5-Fluorouracil: fourty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs 2000; 18: 299–313.

    Article  CAS  PubMed  Google Scholar 

  16. Tanaka F, Fukuse T, Wada H, Fukushima M . The history, mechanism and clinical use of oral 5-fluorouracil derivative chemotherapeutic agents. Curr Pharm Biotechnol 2000; 1: 137–164.

    Article  CAS  PubMed  Google Scholar 

  17. Mader RM, Muller M, Steger GG . Resistance to 5-fluorouracil. Gen Pharmacol 1998; 31: 661–666.

    Article  CAS  PubMed  Google Scholar 

  18. Thomas DM, Zalcberg JR . 5-fluorouracil: a pharmacological paradigm in the use of cytotoxics. Clin Exp Pharmacol Physiol 1998; 25: 887–895.

    Article  CAS  PubMed  Google Scholar 

  19. Kornmann M, Schwabe W, Sander S, Kron M, Strater J, Polat S et al. Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression levels: predictors for survival in colorectal cancer patients receiving adjuvant 5-fluorouracil. Clin Cancer Res 2003; 9: 4116–4124.

    CAS  PubMed  Google Scholar 

  20. Peters GJ, Backus HH, Freemantle S, van Triest B, Codacci-Pisanelli G, van der Wilt CL et al. Introduction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochim Biophys Acta 2002; 1587: 194–205.

    Article  CAS  PubMed  Google Scholar 

  21. Nyati MK, Symon Z, Kievit E, Dornfeld KJ, Rynkiewicz SD, Ross BD et al. The potential of 5-fluorocytosine/cytosine deaminase enzyme prodrug gene therapy in an intrahepatic colon cancer model. Gene Therapy 2002; 9: 844–849.

    Article  CAS  PubMed  Google Scholar 

  22. Miller CR, Williams CR, Buchsbaum DJ, Gillespie GY . Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas. Cancer Res 2002; 62: 773–780.

    CAS  PubMed  Google Scholar 

  23. Kato H, Koshida K, Yokoyama K, Mizokami A, Namiki M . Potential benefits of combining cytosine deaminase/5-fluorocytosine gene therapy and irradiation for prostate cancer: experimental study. Int J Urol 2002; 9: 567–576.

    Article  CAS  PubMed  Google Scholar 

  24. Kurosumi K, Tamiya T, Ono Y, Otsuka S, Kambara H, Adachi Y et al. Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for human malignant glioma cells mediated by adenovirus. J Neurooncol 2004; 66: 117–127.

    Article  Google Scholar 

  25. Erbs P, Regulier E, Kintz J, Leroy P, Poitevin Y, Exinger F et al. In vivo cancer gene therapy by adenovirus-mediated transfer of a bifunctional yeast cytosine deaminase/uracil phosphoribosyltransferase fusion gene. Cancer Res 2000; 60: 3813–3822.

    CAS  PubMed  Google Scholar 

  26. Richard C, Matthews D, Duivenvoorden W, Yau J, Wright PS, Th'ng JPH . Flavopiridol sensitivity of cancer cells isolated from ascites and pleural fluids. Clin Cancer Res 2005; 11: 3523–3529.

    Article  CAS  PubMed  Google Scholar 

  27. Mosmann T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immuno Methods 1983; 65: 55–63.

    Article  CAS  Google Scholar 

  28. Maxwell PJ, Longley DB, Latif T, Boyer J, Allen W, Lynch M et al. Identification of 5-fluorouracil-inducible target genes using cDNA microarray profiling. Cancer Res 2003; 63: 4602–4606.

    CAS  PubMed  Google Scholar 

  29. Shi X, Liu S, Kleeff J, Friess H, Buchler MW . Acquired resistance of pancreatic cancer cells towards 5-fluorouracil and gemcitabine is associated with altered expression of apoptosis-regulating genes. Oncology 2002; 62: 354–362.

    Article  CAS  PubMed  Google Scholar 

  30. Boyer J, McLean EG, Aroori S, Wilson P, McCulla A, Carey PD et al. Characterization of p53 wild-type and null isogenic colorectal cancer cell lines resistant to 5-fluorouracil, oxaliplatin, and irinotecan. Clin Cancer Res 2004; 10: 2158–2167.

    Article  CAS  PubMed  Google Scholar 

  31. Akbulut H, Tang Y, Maynard J, Zhang L, Pizzorno G, Deisseroth A . Vector targeting makes 5-fluorouracil chemotherapy less toxic and more effective in animal models of epithelial neoplasms. Clin Cancer Res 2004; 10: 7738–7746.

    Article  CAS  PubMed  Google Scholar 

  32. Chung YM, Park SH, Park JK, Kim YT, Kang YK, Yoo YD . Establishment and characterization of 5-fluorouracil-resistant gastric cancer cells. Cancer Lett 2000; 159: 95–101.

    Article  CAS  PubMed  Google Scholar 

  33. Ichikawa W, Uetake H, Shirota Y, Yamada H, Takahashi T, Nihei Z et al. Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. Br J Cancer 2003; 89: 1486–1492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Disclosure of source of funds: This work was funded by grants from the Canadian Institute of Health Research (JT and WD) and the Prostate Cancer Research Foundation of Canada (WD).

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Authors and Affiliations

  1. Regional Cancer Program, Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada

    C Richard, W Duivenvoorden & J Th'ng

  2. Departments of Biology and Chemistry, Lakehead University, Thunder Bay, Ontario, Canada

    C Richard, W Duivenvoorden & J Th'ng

  3. Groupe de Vecteurs de Génomique et Thérapie Génique, Biotechnology Research Institute, National Research Council, Montréal, Quebec, Canada

    D Bourbeau & B Massie

  4. INRS-IAF, Université du Québec, Laval, Quebec, Canada

    B Massie

  5. Département de Microbiologie et Immunologie, Faculté de Médecine, Université de Montréal, Quebec, Canada

    B Massie

  6. Department of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada

    W Roa

  7. Division of General Internal Medicine, University of Calgary, Alberta, Canada

    J Yau

  8. Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada

    J Th'ng

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  1. C Richard
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Correspondence to J Th'ng.

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Richard, C., Duivenvoorden, W., Bourbeau, D. et al. Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy. Cancer Gene Ther 14, 57–65 (2007). https://doi.org/10.1038/sj.cgt.7700980

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  • DOI: https://doi.org/10.1038/sj.cgt.7700980

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