Skip to main content
SpringerLink
Log in

The Role of Herpes Simplex Thymidine Kinase Gene Transfer in the Drug Treatment of Brain Tumours

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Summary

The ability to alter human tumour cells genetically in vivo provides a variety of new opportunities to selectively destroy malignant cells.

The herpes simplex thymidine kinase gene (HS-tk) confers a sensitivity to the anti herpes drug ganciclovir. Insertion of HS-tk into tumours and subsequent treatment with ganciclovir has successfully eliminated tumours in experimental animal models, despite a less than 100% gene transfer efficiency. This phenomenon, the ‘bystander effect’, allows the destruction of neighbouring tumour cells not transduced with HS-tk. Since there is no gene transfer method that is 100% efficient, the bystander effect makes the possibility of using gene therapy for the treatment of brain tumours a reasonable approach in patients with recurrent or metastatic CNS tumours.

Human experimentation with this approach began in December 1992. Results from an initial trial have shown that the HS-tk/ganciclovir system can selectively destroy tumour cells with minimal toxicity. Despite the bystander effect, the magnitude of the antitumour effect is currently limited by insufficient gene delivery. Since the HS-tk system is a potent method for tumour cell destruction that is not limited by toxicity, further improvements in gene transfer efficiency may allow the development of a clinically useful therapy for the treatment of eNS malignancies.

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. Blaese RM, Culver KW, Anderson WF. The ADA human gene therapy clinical protocol. Hum Gene Ther 1990; 1: 331–62

    Article  PubMed  Google Scholar 

  2. Osborne WRA, Hock RA, Kaleko M. et al. Long-term expression of human adenosine deaminase in mice after transplantation of bone marrow infected with amphotropic retroviral vectors. Hum Gene Ther 1990; 1: 31–41

    Article  PubMed  CAS  Google Scholar 

  3. Blaese RM, Culver KW, Miller AD. et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 1995; 270: 475–80

    Article  PubMed  CAS  Google Scholar 

  4. Culver KW. Gene therapy: a handbook for physicians. NewYork: MA Liebert, 1996

    Google Scholar 

  5. Culver KW, Blaese RM. Gene therapy for cancer. Trends Genet 1994; 10: 174–8

    Article  PubMed  CAS  Google Scholar 

  6. Elion GB. The chemotherapeutic exploitation of virus-specified enzymes. Adv Enz Regulation 1980; 18: 53–66

    Article  CAS  Google Scholar 

  7. Colbere-Garapin F, Chousterman S, Horodniceanu F, et al. Cloning of the active thymidine kinase gene of herpes simplex virus type 1 in Escherichia coli K-12. Proc Natl Acad Sci USA 1979; 76: 3755–9

    Article  PubMed  CAS  Google Scholar 

  8. Faulds D, Heel RC. Ganciclovir: a review of its anti viral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 1990; 39: 597-38

    Article  PubMed  CAS  Google Scholar 

  9. Terry BJ, Cianci CW, Hagen ME. Inhibition of herpes simplex virus type 1 DNA polymerase by [1R(1a,2b,3a)]-9-[2.3-Bis(hydroxymethyl)cyclobutyl)guanine. Mol Pharm 1991; 40: 591–6

    CAS  Google Scholar 

  10. Smee DF, Martin JC, Verheyden JPH, et al. Anti-herpesvirus activity of the acyclic nucleoside 9-(l,3-dihydroxy-2-propoxymethyl)guanine. Antimicrob Agents Chemother 1983; 23: 676–82

    Article  PubMed  CAS  Google Scholar 

  11. Samejima Y, Meruelo D. ‘Bystander killing’ induces apoptosis and is inhibited by forskolin: plasmid pXtk construction for thymidine-kinase gene transfer to investigate bystander killing. Gene Ther 1995; 2: 50–8

    PubMed  CAS  Google Scholar 

  12. Field AK, Davies ME, DeWitt C, et al. 9-([2-hydroxy-1( hyroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci USA 1983; 80: 4139–43

    Article  PubMed  CAS  Google Scholar 

  13. Gutierrez AA, Lemoine NR, Sikora K. Gene therapy for cancer. Lancet 1992; 339: 715–21

    Article  PubMed  CAS  Google Scholar 

  14. Moolten FL. Tumor sensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a perspective cancer control strategy. Cancer Res 1986; 46: 5276–81

    PubMed  CAS  Google Scholar 

  15. Ezzedine ZD, Martuza RL, Platika D, et al. Selective killing of glioma cells in culture and in vivo by retrovirus transfer of the herpes simplex virus thymidine kinase gene. New Biol 1991; 3: 608–14

    CAS  Google Scholar 

  16. Moolten FL, Wells JM, Heyman RA, et al. Lymphoma regression induced by ganciclovir in mice bearing a herpes thymidine kinase transgene. Hum Gene Ther 1990; 1: 125–34

    Article  PubMed  CAS  Google Scholar 

  17. Smee DF, Boehme R, Chernow M. et al. Intracellular metabolism and enzymatic phosphorylation of 9-( 1,3-dihydroxy-2-propoxymethyl)guanine and acyclovir in herpes simplex virus-infected and uninfected cells. Biochem Pharmacol 1985; 34: 1049–56

    Article  PubMed  CAS  Google Scholar 

  18. Cheng Y-C, Grill SP, Dutschman GE, et al. Metabolism of 9- (1,3-dihydroxy-2-propoxymethyl)guanine, a new anti-herpes virus compound in herpes-simplex virus-infected cells. J Bioil Chem 1983; 258: 12460–4

    CAS  Google Scholar 

  19. Shepp DH, Dandliker PS, de Miranda P, et al. Activity of9-[2- hydroxy-1-(hydroxy-methyl)ethoxymethyl]guanine in the treatment of cytomegalovirus pneumonia. Ann Int Med 1985; 103: 368–73

    PubMed  CAS  Google Scholar 

  20. Stankus BJ. Cytovene product monograph. Palo Alto: Syntex Laboratories Inc., 1992

    Google Scholar 

  21. Salmons B, Gunzburg WH. Targeting of retroviral vectors for gene therapy. Hum Gene Ther 1993; 4: 129–41

    Article  PubMed  CAS  Google Scholar 

  22. Donahue RE, Kessler SW, Bodine D, et al. Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J Exp Med 1992; 176: 1125–35

    Article  PubMed  CAS  Google Scholar 

  23. Ram Z, Culver KW, Walbridge S, et al. In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res 1993; 53: 83–8

    PubMed  CAS  Google Scholar 

  24. Yamada M, Shimizu K, Miayo Y, et al. Retrovirus-mediated gene transfer targeted to malignant glioma cells in murine brain. Jpn J Cancer Res 1992; 83: 1244–7

    Article  PubMed  CAS  Google Scholar 

  25. Short MP, Choi JK, Lee A, et al. Gene delivery to glioma cells in rat brain by grafting of a retrovirus packaging cell line. J Neuroscience Res 1990; 27: 427–33

    Article  CAS  Google Scholar 

  26. Culver KW, Ram Z, Walbridge S, et al. In vivo gene transfer with retroviral vector producer cells for treatment of experimental brain tumors. Science 1992; 256: 1550–2

    Article  PubMed  CAS  Google Scholar 

  27. Barba D, Hardin J, Ray J, et al. Thymidine kinase-mediated killing of rat brain tumors. J Neurosurg 1993; 79: 729–35

    Article  PubMed  CAS  Google Scholar 

  28. Brody SL, Jaffe HA, Han SK, et al. Direct in vivo gene transfer and expression in malignant cells using adenovirus vectors: cancer therapy strategy. Hum Gene Ther 1994; 5: 437–47

    Article  PubMed  CAS  Google Scholar 

  29. Akli S, Caillaud C, Vigne E, et al. Transfer of a foreign gene into the brain using adenovirus vectors. Nature Genet 1993; 3: 224–8

    Article  PubMed  CAS  Google Scholar 

  30. Bajocchi G, Feldman SH, Crystal RG, et al. Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors. Nature Genet 1993; 3: 229–34

    Article  PubMed  CAS  Google Scholar 

  31. Davidson BL, Allen ED, Kozarsky KF, et al. A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nature Genet 1993; 3: 219–23

    Article  PubMed  CAS  Google Scholar 

  32. La Salle GL, Robert JJ, Berrard S, et al. An adenovirus vector for gene transfer into neurons and glia in the brain. Science 1993; 259: 988–90

    Article  Google Scholar 

  33. Smythe WR, Hwang HC, Amin KM, et al. Use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase(HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system. Cancer Res 1994; 54: 2055–9

    PubMed  CAS  Google Scholar 

  34. Bonnekoh B, Greenhalgh DA, Bundham DS, et al. Inhibition of melanoma growth by adenoviral-mediated HSV thymidine kinase gene transfer in vivo. J Invest Dermatol 1995; 104: 313–7

    Article  PubMed  CAS  Google Scholar 

  35. Vile RG, Han IR, In vitro and in vivo targeting of gene expression to melanoma cells. Cancer Res 1993; 53: 962–7

    PubMed  CAS  Google Scholar 

  36. Byrnes AP, Rusby JE, Wood MJA, et al. Adenovirus gene transfer causes inflammation in the brain. Neuroscience 1995; 66: 1015–24

    Article  PubMed  CAS  Google Scholar 

  37. Coen DM, Kosz-Vnenchak M, Jacobson JG, et al. Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate. Proc Natl Acad Sci USA 1989; 86: 4736–40

    Article  PubMed  CAS  Google Scholar 

  38. Boviatsis EJ, Park JS, Sena-Esteves M, et al. Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. Cancer Res 1994; 54: 5745–51

    PubMed  CAS  Google Scholar 

  39. Manuza RL, Malick A, Markert JM, et al. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991; 252: 854–6

    Article  Google Scholar 

  40. Ulmer JB, Donnelly JJ, Parker SE, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 1993; 259: 1745–9

    Article  PubMed  CAS  Google Scholar 

  41. Tang D, DeVit M, Johnston SA, Genetic immunization is a simpie method for eliciting an immune response. Nature 1992; 356: 152–4

    Article  PubMed  CAS  Google Scholar 

  42. Nabel J, Chang A, Nabel EG, et al. Immunotherapy of malignancy by in vivo gene transfer into tumors. Hum Gene Ther 1992; 3: 399–410

    Article  Google Scholar 

  43. Zhu N, Liggitt D, Liu Y, et al. Systemic gene expression after intravenous DNA delivery into adult mice. Science 1993; 261: 209–11

    Article  PubMed  CAS  Google Scholar 

  44. Yoshida J, Mizuno M, Vagi K. Cytotoxicity of human-interferon produced in human glioma cells transfected with its gene by means of liposomes. Biochem Intl 1992; 28: 1055–61

    CAS  Google Scholar 

  45. Wu GY, Wu CH. Receptor-mediated in vitro gene transformation by a soluble DNA carrier system. J Bioi Chem 1987; 262: 4429–32

    CAS  Google Scholar 

  46. Wagner E, Zenke M, Cotten M, et al. Transferrin-polycation conjugates as carriers for DNA uptake into cells. Proc Natl Acad Sci USA 1990; 87: 3410–4

    Article  PubMed  CAS  Google Scholar 

  47. Jiao S, Cheng L, Wolff JA, et al. Particle bombardment-mediated gene transfer and expression in rat brain tissues. Biotechnology 1993; 11: 497–502

    Article  PubMed  CAS  Google Scholar 

  48. Bi WL, Parysek LM, Warnick R, et al. In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy. Hum Gene Ther 1993; 4: 725–31

    Article  PubMed  CAS  Google Scholar 

  49. Fick J, Barker FGII, Dazin P, et al. The extent of heterocellular communication mediated by gap junctions is predictivebystander tumor cytotoxicity in vitro. Proc Natl Acad Sci USA 1995: 92: 11071–5

    Article  PubMed  CAS  Google Scholar 

  50. Elshami AA, Saavedra A, Zhang H. et al. Gap junctions play a role in the ‘bystander effect’ of the herpes simplex virus thymidine kinase/ganciclovir system in vitro. Gene Ther 1996::3: 85–92

    PubMed  CAS  Google Scholar 

  51. Hooper ML, Subak-Sharpe JH. Metabolic cooperation between cells. Int Rev Cytol 1991: 69: 45–104

    Article  Google Scholar 

  52. Plautz G, Nabel EG, Nabel GJ. Selective elimination of recombinant genes in vivo with a suicide retroviral vector. New Biol 1991: 7: 709–15

    Google Scholar 

  53. Chen S-H, Shine HD, Goodman JC, et al. Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci USA 1994; 91: 3054–7

    Article  PubMed  CAS  Google Scholar 

  54. Freeman SM, Abbou CN, Whartenby KA, et al. The ‘bystander effect’: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53: 5274–83

    PubMed  CAS  Google Scholar 

  55. Ram Z, Walbridge S, Shawker T, et al. The effect of thymidine kinase transduction and ganciclovir therapy on tumor vasculature and growth of 9L gliomas in rats. J Neurosurg 1994; 81: 256–60

    Article  PubMed  CAS  Google Scholar 

  56. Wu JK, Cano WG, Meylaerts SAG, et al. Bystander tumoricidal effect in the treatment of experimental brain tumors. Neurosurgery 1994: 35: 1094–103

    Article  PubMed  CAS  Google Scholar 

  57. Culver KW, Moorman DW, Muldoon RR, et al. Toxicity and immunologic effects of in vivo retrovirus-mediated gene transfer of the herpes simplex-thymidine kinase gene into solid tumors. Cold Spring Harb Symp on Quant Biol 1994: 59: 683–90

    Google Scholar 

  58. Weisacker M, Deen DF, Rosenblum ML, et al. The 9L rat brain tumor model: description and application of the model. J Neurol 1981: 224: 183–92

    Article  Google Scholar 

  59. Ram Z, Culver KW, Walbridge S, et al. Toxicity studies of retroviral-mediated gene transfer for the treatment of brain tumors. J Neurosurg 1993: 79: 400–7

    Article  PubMed  CAS  Google Scholar 

  60. Oldfield EH, Ram Z, Culver KW, et al. A clinical protocol: gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and in travenous ganciclovir. Hum Gene Ther 1993: 4: 39–69

    Article  PubMed  CAS  Google Scholar 

  61. Culver KW, Van Gilder J, Link Jr CJ, et al. Gene therapy for the treatment of malignant brain tumors with in vivo tumor transduction with the herpes simplex thymidine kinase gene/ganciclovir system. Hum Gene Ther 1993: 5: 343–77

    Article  Google Scholar 

  62. Raffel C, Culver KW, Kohn D, et al. Gene therapy for the treatment of recurrent pediatric malignant astrocytomas using in vivo tumor transduction with the herpes simplex thymidine kinase gene/ganciclovir system. Hum Gene Ther 1994; 5: 863–90

    Article  PubMed  CAS  Google Scholar 

  63. Oldfield EH, Ram Z, Chiang Y, et al. Intrathecal gene therapy for the treatment of leptomeningeal carcinomatosis: a phase I/II study. Hum Gene Ther 1995; 6: 55–85

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Gene Therapy Research and Clinical Affairs, OncorPharm, Inc, 200 Perry Parkway, Gaithersburg, Maryland, 20877, USA

    Kenneth W. Culver (Director)

Authors
  1. Kenneth W. Culver
    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

Culver, K.W. The Role of Herpes Simplex Thymidine Kinase Gene Transfer in the Drug Treatment of Brain Tumours. CNS Drugs 6, 1–11 (1996). https://doi.org/10.2165/00023210-199606010-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-199606010-00001

Keywords

Search

Navigation