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Enhanced pancreatic tumor regression by a combination of adenovirus and retrovirus-mediated delivery of the herpes simplex virus thymidine kinase gene

Gene Therapy volume 6, pages 547–553 (1999)Cite this article

Abstract

We have evaluated the effectiveness of combining the different characteristics of retrovirus and adenovirus to apply the herpes simplex virus thymidine kinase gene (HSVtk) and ganciclovir (GCV) treatment for gene therapy of pancreatic cancer. Transduction of NP-18 human pancreatic cells in culture by either the adenoviral vector (ADV/tk) or the retroviral vector (Rv/tk) followed by GCV treatment resulted in a GCV dose-dependent cytotoxic effect. A bystander effect was determined, both in NP-18 cultures and in xenogeneic cell mixtures of NP-18 and PA317 cells. Studies in vivo indicated that the effectiveness of tumor regression after HSVtk gene transfer and GCV treatment was dependent first on the tumor size at the time of viral injection and secondly, in large tumors, on the type of virus administered. The administration of the viral combination (ADV/tk + vector producer cells VPC-Rv/tk) was the best approach tested and resulted in a dramatic reduction in tumor mass after 4 days of GCV treatment which was maintained for the treatment period. Remarkably, two animals presented a complete eradication of the tumor. Thus, the HSVtk/GCV system when administered using a viral combination (ADV/tk + VPC-Rv/tk), may be a promising suicide gene therapy for pancreatic carcinomas.

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References

  1. Warshaw AL, Fernandez-del Castillo C . Pancreatic carcinoma New Engl J Med 1992 326: 455–465

    Article  CAS  PubMed  Google Scholar 

  2. Beger HG, Link KH, Poch B, Gansauge F . Pancreatic cancer recent progress in diagnosis and treatment In: Neoptolemos JP, Lemoine NR (eds) . Pancreatic Cancer. Molecular and Clinical Advances Blackwell: Oxford 1996 pp 227–235

    Google Scholar 

  3. Rigg A, Sikora K . Genetic prodrug activation therapy Mol Med Today 1997 3: 359–366

    Article  CAS  PubMed  Google Scholar 

  4. Cheng YC et al. Unique spectrum of activity of 9-{(1,3-dihydroxy-2-propoxy)methyl}-guanine against herpes viruses in vitro and its mode of action against herpes symplex virus type 1 Proc Natl Acad Sci USA 1983 80: 2167–2770

    Article  Google Scholar 

  5. Caruso M . Gene therapy against cancer and HIV infection using the gene encoding herpes simplex virus thymidine kinase Mol Med Today 1996 2: 212–217

    Article  CAS  PubMed  Google Scholar 

  6. Culver KW et al. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors Science 1992 256: 1550–1552

    Article  CAS  PubMed  Google Scholar 

  7. Gagandeep S et al. Prodrug-activated gene therapy: involvement of an immunological component in the ‘bystander effect’ Cancer Gene Ther 1996 3: 83–88

    CAS  PubMed  Google Scholar 

  8. Colombo BM et al. 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 Ther 1995 6: 763–772

    Article  CAS  PubMed  Google Scholar 

  9. Elshami AA et al. Gap junctions play a role in the bystander effect of the herpes simplex virus thymidine kinase/ganciclovir system in vitro Gene Therapy 1996 3: 85–92

    CAS  PubMed  Google Scholar 

  10. Vrionis FD et al. The bystander effect exerted by tumor cells expressing the herpes simplex virus thymidine kinase (HSVtk) gene is dependent on connexin expression and cell communication via gap junctions Gene Therapy 1997 4: 577–585

    Article  CAS  PubMed  Google Scholar 

  11. Ram Z et al. In situ retrovirus-mediated gene transfer for the treatment of brain tumors in rats Cancer Res 1993 53: 83–88

    CAS  PubMed  Google Scholar 

  12. Eastham JA et al. Prostate cancer gene therapy: herpes simplex virus thymidine kinase gene transduction followed by Ganciclovir in mouse and human prostate cancer models Hum Gene Ther 1996 7: 515–523

    Article  CAS  PubMed  Google Scholar 

  13. Haffe HA et al. Adenovirus-mediated in vivo gene transfer and expression in normal rat liver Nat Genet 1992 1: 372–378

    Article  Google Scholar 

  14. Takamiya Y et al. An experimental model of retrovirus gene therapy for malignant brain tumors J Neurosurg 1993 79: 104–110

    Article  CAS  PubMed  Google Scholar 

  15. Feng M et al. Stable in vivo gene transduction via a novel adenoviral/retroviral chimeric vector Nat Biotechnol 1997 15: 866–870

    Article  CAS  PubMed  Google Scholar 

  16. Garcia C et al. Characterization of new human pancreatic cancer cell lines expressing p21 and Gadd45 by p53-independent pathways Cancer Res 1998 (submitted)

  17. Ishii-morita H et al. Mechanism of bystander effect killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment Gene Therapy 1997 4: 244–251

    Article  CAS  PubMed  Google Scholar 

  18. DiMaio JM et al. Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo Surgery 1994 116: 205–213

    CAS  PubMed  Google Scholar 

  19. Rosenfeld ME et al. Pancreatic carcinoma cell killing via adenoviral mediated delivery of herpes simplex virus thymidine kinase gene Ann Surg 1997 225: 609–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smiley WR et al. Establishment of parameters for optimal transduction efficiency and antitumor effects with purified high-titer HSVtk retroviral vector in established solid tumors Hum Gene Ther 1997 8: 965–977

    Article  CAS  PubMed  Google Scholar 

  21. Kuriyama S et al. Tissue-specific expression of HSVtk gene can induce efficient antitumor effect and protective immunity to wild-type hepatocellular carcinoma Int J Cancer 1997 71: 470–475

    Article  CAS  PubMed  Google Scholar 

  22. Link CJ, Moorman D . A phase I trial of in vivo gene therapy with the herpes simplex thymidine kinase/ganciclovir system for the treatment of refractory or recurrent ovarian cancer Hum Gene Ther 1996 7: 1161–1179

    Article  PubMed  Google Scholar 

  23. Becker TC et al. Use of recombinant adenovirus for metabolic engineering of mammalian cells Meth Cell Biol 1994 43: 161–189

    Article  CAS  Google Scholar 

  24. Izquierdo M et al. Long-term rat survival after malignant brain tumor regression by retroviral gene therapy Gene Therapy 1995 2: 66–69

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Centre de Genètica Mèdica i Molecular, Institut de Recerca Oncològica (IRO), Barcelona, Spain

    M Carrió, M Nadal & C Fillat

  2. Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain

    A Romagosa, A Mazo & A-M Gómez-Foix

  3. Departament de Microbiologia, Universitat de Barcelona, Barcelona, Spain

    E Mercadé

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  1. M Carrió
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  2. A Romagosa
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  4. A Mazo
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Carrió, M., Romagosa, A., Mercadé, E. et al. Enhanced pancreatic tumor regression by a combination of adenovirus and retrovirus-mediated delivery of the herpes simplex virus thymidine kinase gene. Gene Ther 6, 547–553 (1999). https://doi.org/10.1038/sj.gt.3300846

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  • DOI: https://doi.org/10.1038/sj.gt.3300846

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