Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Acquired Diseases
  • Published:

Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression

Gene Therapy volume 7, pages 1217–1223 (2000)Cite this article

Abstract

replicating viruses for cancer gene therapy have beneficial antitumor effects, however, in the setting of an enzyme/prodrug system, the interactions between these viruses and the activated agents are complex. a replicating vaccinia virus expressing the cytosine deaminase gene (vvcd), which converts the prodrug 5-fc into 5-fu, was characterized in vitro and in vivo for its antitumor effects and pathogenicity. replicating vvcd (±5-fc) at various mois was used to infect mc38 murine colon adenocarcinoma cells. at high mois (>0.1) virus alone was able to kill the majority (65–90%) of cells by day 5 with no additional benefit from prodrug. At low MOIs only the effect of prodrug is seen. Cell lysates demonstrated 300-fold reduced viral recovery from cells treated with both VVCD and 5-FC compared with controls treated with virus alone. Nude mice bearing subcutaneous MC38 tumors were injected with VVCD (or control) and treated with 5FC or control. Mice injected with VVCD (with or without 5FC treatment) had smaller tumors than the controls, suggesting that replicating vaccinia alone is cytotoxic to tumors in vivo. The addition of 5-FC improved the antitumor response when a low dose of virus was injected into tumors. Also, compared with mice that received virus alone, those that received VVCD and 5FC had significantly prolonged survival from virus-mediated death. In conclusion, the addition of an enzyme/prodrug system to a replicating virus can improve the antitumor response and decrease viral pathogenicity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Siders WM, Halloran PJ, Fenton RG . Transcriptional targeting of recombinant adenoviruses to human and murine melanoma cells Cancer Res 1996 56: 5638–5646

    CAS  PubMed  Google Scholar 

  2. Parr MJ et al. Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector Nature Med 1997 3: 1145–1149

    Article  CAS  PubMed  Google Scholar 

  3. Dmitriev I et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism J Virol 1998 72: 9706–9713

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Park BJ et al. Augmentation of melanoma-specific gene expression using a tandem melanocyte-specific enhancer results in increased cytotoxicity of the purine nucleoside phosphorylase gene in melanoma Hum Gene Ther 1999 10: 889–898

    Article  CAS  PubMed  Google Scholar 

  5. Martuza RL et al. Experimental therapy of human glioma by means of a genetically engineered virus mutant Science 1991 252: 854–856

    Article  CAS  PubMed  Google Scholar 

  6. Heise C et al. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents Nature Med 1997 3: 639–645

    Article  CAS  PubMed  Google Scholar 

  7. Advani SJ et al. Replication-competent, nonneuroinvasive genetically engineered herpes virus is highly effective in the treatment of therapy-resistant experimental human tumors Cancer Res 1999 59: 2055–2058

    CAS  PubMed  Google Scholar 

  8. Walker JR et al. Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207 Hum Gene Ther 1999 10: 2237–2243

    Article  CAS  PubMed  Google Scholar 

  9. Lane DP . Killing tumor cells with viruses – a question of specificity Nat Med 1998 4: 1012–1013

    Article  CAS  PubMed  Google Scholar 

  10. Miyatake S-I, Martuza RL, Rabkin SD . Defective herpes simplex virus vectors expressing thymidine kinase for the treatment of malignant glioma Cancer Gene Ther 1997 4: 222–228

    CAS  PubMed  Google Scholar 

  11. Chase M, Chung RY, Chiocca EA . An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy Nat Biotechnol 1998 16: 444–448

    Article  CAS  PubMed  Google Scholar 

  12. Wildner O, Blaese RM, Morris JC . Therapy of colon cancer with oncolytic adenovirus is enhanced by the addition of herpes simplex virus-thymidine kinase Cancer Res 1999 59: 410–413

    CAS  PubMed  Google Scholar 

  13. Aghi M et al. Multimodal cancer treatment mediated by a replicating oncolytic virus that delivers the oxazaphosphorine/rat cytochrome P450 2B1 and ganciclovir-herpes simplex virus thymidine kinase gene therapies Cancer Res 1999 59: 3861–3865

    CAS  PubMed  Google Scholar 

  14. Carroll MW, Moss B . Poxviruses as expression vectors Curr Opin Biotechnol 1997 8: 573–577

    Article  CAS  PubMed  Google Scholar 

  15. Peplinski GR, Tsung K, Norton JA . Vaccinia virus for human gene therapy Surg Oncol Clin North Am 1998 7: 575–588

    Article  CAS  Google Scholar 

  16. Moss B . Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety Proc Natl Acad Sci USA 1996 93: 11341–11348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Buller RM et al. Decreased virulence of recombinant vaccinia virus expression vectors is associated with a thymidine kinase-negative phenotype Nature 1985 317: 813–815

    Article  CAS  PubMed  Google Scholar 

  18. Gnant MFX, Puhlmann M, Alexander HR Jr, Bartlett DL . Systemic administration of a recombinant vaccinia virus expressing the cytosine deaminase gene and subsequent treatment with 5-fluorocytosine leads to tumor specific gene expression and prolongation of survival in mice Cancer Res 1999 59: 3396–3404

    CAS  PubMed  Google Scholar 

  19. Puhlmann M et al. Thymidine kinase deleted vaccinia virus expressing purine nucleoside phosphorylase as a vector for tumor directed gene therapy Hum Gene Ther 1999 10: 649–657

    Article  CAS  PubMed  Google Scholar 

  20. Bischoff JR et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells (see comments) Science 1996 274: 373–376

    Article  CAS  PubMed  Google Scholar 

  21. Nicolo M, Chiocca EA . Marker gene transfer and oncolysis of human Y79 retinoblastoma cells mediated by herpes simplex virus mutants Ophthalmic Res 1998 30: 30–36

    Article  CAS  PubMed  Google Scholar 

  22. Andreansky S et al. Evaluation of genetically engineered herpes simplex viruses as oncolytic agents for human malignant brain tumors Cancer Res 1997 57: 1502–1509

    CAS  PubMed  Google Scholar 

  23. Chakrabarti S, Sisler JR, Moss B . Compact, synthetic, vaccinia virus early/late promoter for protein expression BioTechniques 1997 23: 1094–1097

    Article  CAS  PubMed  Google Scholar 

  24. Davison AJ, Moss B . Structure of vaccinia virus late promoters J Mol Biol 1989 210: 771–784

    Article  CAS  PubMed  Google Scholar 

  25. Davison AJ, Moss B . Structure of vaccinia virus early promoters J Mol Biol 1989 210: 749–769

    Article  CAS  PubMed  Google Scholar 

  26. Puhlmann M et al. Vaccinia as a vector for tumor directed gene therapy: biodistribution of a thymidine kinase deleted mutant Cancer Gene Ther 2000 7: 66–73

    Article  CAS  PubMed  Google Scholar 

  27. Trinh QT et al. Enzyme-prodrug gene therapy: comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase-ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line Cancer Res 1995 55: 4808–4812

    CAS  PubMed  Google Scholar 

  28. Huber BE et al. 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 1994 91: 8302–8306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hirschowitz EA et al. 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 Ther 1995 6: 1055–1063

    Article  CAS  PubMed  Google Scholar 

  30. Ohwada A, Hirschowitz EA, Crystal RG . Regional delivery of an adenovirus vector containing the Escherichia coli cytosine deaminase gene to provide local activation of 5-fluorocytosine to suppress the growth of colon carcinoma metastatic to liver Hum Gene Ther 1996 7: 1567–1576

    Article  CAS  PubMed  Google Scholar 

  31. Topf N, Worgall S, Hackett NR, Crystal RG . Regional ‘pro-drug’ gene therapy: intravenous administration of an adenoviral vector expressing the E. coli cytosine deaminase gene and systemic administration of 5-fluorocytosine suppresses growth of hepatic metastasis of colon carcinoma Gene Therapy 1998 5: 507–513

    Article  CAS  PubMed  Google Scholar 

  32. Gnant M, Puhlmann M, Bartlett DL, Alexander HR . Regional versus systemic delivery of recombinant vaccinia virus as suicide gene therapy for murine liver metastases Ann Surg 1999 230: 352–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Huber BE, Richards CA, Austin EA . Virus-directed enzyme/prodrug therapy (VDEPT) Ann NY Acad Sci 1994 716: 104–114

    Article  CAS  PubMed  Google Scholar 

  34. Earl PL, Moss B . Expression of proteins in mammalian cells using vaccinia viral vectors. In: Ausubel FM et al (eds) Current Protocols in Molecular Biology John Wiley: New York 1998 pp 16.15.1–16.18.11

    Google Scholar 

  35. O'Reilly MS et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth Cell 1997 88: 277–285

    Article  CAS  PubMed  Google Scholar 

  36. Kaplan EL, Meier P . Non-parametric estimation from incomplete observation J Am Stat Assoc 1958 53: 457–481

    Article  Google Scholar 

  37. Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration Cancer Chemother Rep 1966 50: 163–170

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Drs Charles Brown, Peter Wu and James Huang for their assistance with this work.

Author information

Authors and Affiliations

  1. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    JA McCart, M Puhlmann, J Lee, Y Hu, SK Libutti, HR Alexander & DL Bartlett

Authors
  1. JA McCart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Puhlmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. SK Libutti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. HR Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. DL Bartlett
    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

McCart, J., Puhlmann, M., Lee, J. et al. Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression. Gene Ther 7, 1217–1223 (2000). https://doi.org/10.1038/sj.gt.3301237

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301237

Keywords

This article is cited by

Search

Advanced search

Quick links