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.

  • Paper
  • Published:

Hepatoma-specific antitumor activity of an albumin enhancer/promoter regulated herpes simplex virus in vivo

Abstract

Targeting viral vectors to appropriate cell types so that normal cells are not adversely affected is an important goal for gene therapy. Previously, we described a novel approach to viral gene therapy using a conditional, replication-competent herpes simplex virus (HSV), where replication and associated cytotoxicity are limited to a specific cell-type by the regulated expression of an essential immediate–early viral gene product. In this report we analyze the hepatoma-specific replication, cytotoxicity and anti-tumor effect of recombinant HSV G92A, regulated by the albumin enhancer/promoter. G92A efficiently replicated in vitro in two human hepatoma cell lines expressing albumin, but not in four human non-hepatoma, albumin-non- expressing tumor cell lines, while all cell lines were equally susceptible to a tissue nonspecific HSV recombinant, hrR3. In vivo, G92A replicated well in subcutaneous xenografts of human hepatoma cells (Hep3B) in athymic mice, but not in non-hepatoma subcutaneous tumors (PC3 and HeLa), whereas, hrR3 replicated well in both tumor types. Intratumoral inoculation of G92A inhibited the growth of established subcutaneous hepatoma tumors in nude mice, but not prostate tumors. Replication-competent viral vectors controlled by cell-specific transcriptional regulatory sequences provide a new therapeutic strategy for tumor therapy.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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. Gutierrez AA, Lemoine NR, Sikora K . Gene therapy for cancer Lancet 1992 339: 715–721

    Article  CAS  PubMed  Google Scholar 

  2. Moolten FL . Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy Cancer Res 1986 46: 5276–5281

    CAS  PubMed  Google Scholar 

  3. Freeman SM et al. In situ use of suicide genes for cancer therapy Semin Oncol 1996 23: 31–45

    CAS  PubMed  Google Scholar 

  4. Schmidt-Wolf G, Schmidt-Wolf IGH . Cytokines and clinical gene therapy Eur J Immunol 1995 25: 1137–1140

    Article  CAS  PubMed  Google Scholar 

  5. Musiani P et al. Cytokines, tumor-cell death and immunogenicity: a question of choice Immunol Today 1997 18: 32–36

    Article  CAS  PubMed  Google Scholar 

  6. Roth JA et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer Nature Med 1996 2: 985–991

    Article  CAS  PubMed  Google Scholar 

  7. Xu HJ et al. Enhanced tumor suppressor gene therapy via replication-deficient adenovirus vectors expressing an N-terminal truncated retinoblastoma protein Cancer Res 1996 56: 2245–2249

    CAS  PubMed  Google Scholar 

  8. Mineta T et al. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas Nature Med 1995 1: 938–943

    Article  CAS  PubMed  Google Scholar 

  9. Yazaki T, Manz HJ, Rabkin SD, Martuza RL . Treatment of human malignant meningiomas by G207, a replication-competent multimutated herpes simplex virus 1 Cancer Res 1995 55: 4752–4756

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Kasahara N, Dozy AM, Kan YW . Tissue-specific targeting of retroviral vectors through ligand–receptor interactions Science 1994 266: 1373–1376

    Article  CAS  PubMed  Google Scholar 

  12. Somia NV, Zoppe M, Verma IM . Generation of targeted retroviral vectors by using single-chain variable fragment: an approach to in vivo gene therapy Proc Natl Acad Sci USA 1995 92: 7570–7574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Miller N, Vile R . Targeted vectors for gene therapy FASEB J 1995 9: 190–199

    Article  CAS  PubMed  Google Scholar 

  14. Huber BE, Richards CA, Krenitsky TA . Retrovirus-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy Proc Natl Acad Sci USA 1991 88: 8039–8043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kuriyama S et al. A potential approach for gene therapy targeting hepatoma using a liver-specific promoter on a retroviral vector Cell Struct Funct 1991 16: 503–510

    Article  CAS  PubMed  Google Scholar 

  16. Vile RG, Hart IR . Use of tissue-specific expression of the herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intratumoral injection of DNA Cancer Res 1993 53: 3860–3864

    CAS  PubMed  Google Scholar 

  17. Rodriguez R et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells Cancer Res 1997 57: 2559–2563

    CAS  PubMed  Google Scholar 

  18. Wright TL, Venook AP, Millward-Sadler GH . Hepatic tumors In: Millward-Sadler GH, Wright R, Arthur MJP (eds) . Wright’s Liver and Biliary Disease 3rd edn: WB Saunders: London 1992 pp 1079–1121

    Google Scholar 

  19. Sherman M . Hepatocellular carcinoma Gastroenterologist 1995 3: 55–66

    CAS  PubMed  Google Scholar 

  20. Farmer DG, Rosove MH, Shaked A, Busuttil RW . Current treatment modalities for hepatocellular carcinoma Ann Surg 1994 219: 236–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu CL, Fan ST . Nonresectional therapies for hepatocellular carcinoma Am J Surg 1997 173: 358–365

    Article  CAS  PubMed  Google Scholar 

  22. Simonetti RG, Liberati A, Angiolini C, Pagliaro L . Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials Ann Oncol 1997 8: 117–136

    Article  CAS  PubMed  Google Scholar 

  23. Markert JM, Malick A, Coen DM, Martuza RL . Reduction and elimination of encephalitis in an experimental glioma therapy model with attenuated herpes simplex mutants that retain susceptibility to acyclovir Neurosurgery 1993 32: 597–603

    Article  CAS  PubMed  Google Scholar 

  24. 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 

  25. Mineta T, Rabkin SD, Martuza RL . Treatment of malignantgliomas using ganciclovir-hypersensitive, ribonucleotide reductase-deficient herpes simplex viral mutant Cancer Res 1994 54: 3963–3966

    CAS  PubMed  Google Scholar 

  26. Andreansky SS et al. The application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors Proc Natl Acad Sci USA 1996 93: 11313–11318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Randazzo BP et al. Treatment of experimental intracranial murine melanoma with a neuroattenuated herpes simplex virus 1 mutant Virology 1995 211: 94–101

    Article  CAS  PubMed  Google Scholar 

  28. Boviatsis EJ 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: 5745–5751

    CAS  PubMed  Google Scholar 

  29. Pyles RB et al. A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors Hum Gene Ther 1997 8: 533–544

    Article  CAS  PubMed  Google Scholar 

  30. Miyatake S-I, Iyer A, Martuza RL, Rabkin SD . Transcriptional targeting of herpes simplex virus for cell-specific replication J Virol 1997 71: 5124–5132

    CAS  PubMed  PubMed Central  Google Scholar 

  31. DeLuca NA, McCarthy AM, Schaffer PA . Isolation and characterization of deletion mutants of herpes simplex virus type 1 in the gene encoding immediate–early regulatory protein ICP4 J Virol 1985 56: 558–570

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Leopardi R, Van Sant C, Roizman B . The herpes simplex virus 1 protein kinase US3 is required for protection from apoptosis induced by the virus Proc Natl Acad Sci USA 1997 94: 7891–7896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Meignier B et al. Virulence of and establishment of latency by genetically engineered deletion mutants of herpes simplex virus Virology 1988 162: 251–254

    Article  CAS  PubMed  Google Scholar 

  34. Powell DJ et al. Transcriptional and post-transcriptional control of specific messenger RNAs in adult and embryonic liver J Mol Biol 1984 179: 21–35

    Article  CAS  PubMed  Google Scholar 

  35. Kudo T (ed) . List of Transplantable Tumors Maintained in Japan Institute of Development, Aging and Cancer: Tohoku University 1996

    Google Scholar 

  36. Arai T, Okamoto K, Ishiguro K, Terao K . HeLa cell tumor in nude mice and its response to antitumor agents Gann 1976 67: 493–503

    CAS  PubMed  Google Scholar 

  37. Ware JL, Paulson DF, Mickey GH, Webb KS . Spontaneous metastasis of cells of the human prostate carcinoma cell line PC-3 in athymic nude mice J Urol 1982 128: 1064–1067

    Article  CAS  PubMed  Google Scholar 

  38. Johnson PA et al. Cytotoxicity of a replication-defective mutant of herpes simplex virus type 1 J Virol 1992 66: 2952–2965

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu NX, Watkins SC, Schaffer PA, DeLuca NA . Prolonged gene expression and cell survival after infection by a herpes simplex virus mutant defective in the immediate–early genes encoding ICP4, ICP27 and ICP22 J Virol 1996 70: 6358–6369

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Goldstein DJ, Weller SK . Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensible for virus growth and DNA synthesis: isolation and characterization of an ICP6 lacZ insertion mutant J Virol 1988 62: 196–205

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Boviatsis EJ et al. Antitumor activity and reporter gene transfer into rat brain neoplasms inoculated with herpes simplex virus vectors defective in thymidine kinase or ribonucleotide reductase Gene Therapy 1994 1: 323–331

    CAS  PubMed  Google Scholar 

  42. Carroll NM, Chiocca E, Takahashi K, Tanabe KK . Enhancement of gene therapy specificity for diffuse colon carcinoma liver metastases with recombinant herpes simplex virus Ann Surgery 1996 224: 323–330

    Article  CAS  Google Scholar 

  43. Kramm CM et al. Long-term survival in a rodent model of disseminated brain tumors by combined intrathecal delivery of herpes vectors and ganciclovir treatment Hum Gene Ther 1996 7: 1989–1994

    Article  CAS  PubMed  Google Scholar 

  44. Cameron JM et al. Ribonucleotide reductase encoded by herpes simplex virus is a determinant of the pathogenicity of the virus in mice and a valid antiviral target J Gen Virol 1988 69: 2607–2612

    Article  CAS  PubMed  Google Scholar 

  45. Yamada Y et al. The pathogenicity of ribonucleotide reductase-null mutants of herpes simplex virus type 1 in mice J Infect Dis 1991 164: 1091–1097

    Article  CAS  PubMed  Google Scholar 

  46. Turk SR et al. Herpes simplex virus type 1 ribonucleotide reductase null mutants induce lesions in guinea pigs Virology 1989 173: 733–735

    Article  CAS  PubMed  Google Scholar 

  47. Panning B, Smiley JR . Regulation of cellular genes transduced by herpes simplex virus J Virol 1989 63: 1929–1937

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Roemer K, Johnson PA, Friedmann T . Activity of the simian virus 40 early promoter–enhancer in herpes simplex virus type 1 vectors is dependent on its position, the infected cell type, and the presence of Vmw175 J Virol 1991 65: 6900–6912

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Smibert CA, Smiley JR . Differential regulation of endogenous and transduced beta-globin genes during infection of erythroid cells with a herpes simplex virus type 1 recombinant J Virol 1990 64: 3882–94

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sato Y et al. Enhanced and specific gene expression via tissue-specific production of Cre recombinase using adenovirus vector Biochem Biophys Res Commun 1998 244: 455–462

    Article  CAS  PubMed  Google Scholar 

  51. Otsuru A, Nagataki S, Koji T, Tamaoki T . Analysis of alpha-fetoprotein gene expression in hepatocellular carcinoma and liver cirrhosis by in situ hybridization Cancer 1988 62: 1105–1112

    Article  CAS  PubMed  Google Scholar 

  52. Di Bisceglie AM et al. Detection of alpha-foetoprotein messenger RNA in human hepatocellular carcinoma and hepatoblastoma tissue Br J Cancer 1986 54: 779–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Abelev GI . Alpha-fetoprotein in ontogenesis and its association with malignant tumors Adv Cancer Res 1971 14: 295–358

    Article  CAS  PubMed  Google Scholar 

  54. Jamieson AT, Gentry GA, Subak-Sharpe JH . Induction of both thymidine and deoxycytidine kinase activity by herpes viruses J Gen Virol 1974 24: 465–480

    Article  CAS  PubMed  Google Scholar 

  55. Kaplitt MG et al. Mutant herpes simplex virus induced regression of tumors growing in immunocompetent rats J Neuro-Oncol 1994 19: 137–147

    Article  CAS  Google Scholar 

  56. Tenser RB . Role of herpes simplex virus thymidine kinase expression in viral pathogenesis and latency Intervirology 1991 32: 76–92

    Article  CAS  PubMed  Google Scholar 

  57. Fang ZY, Tenser RB, Rapp F . Hepatic infection by thymidine kinase-positive and thymidine kinase-negative herpes simplex virus after partial hepatectomy Infect Immun 1983 42: 402–408

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Andreansky S et al. Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins Gene Therapy 1998 5: 121–130

    Article  CAS  PubMed  Google Scholar 

  59. 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 

  60. Toda M, Martuza RL, Kojima H, Rabkin SD . In situ cancer vaccination: an IL-12 defective vector/replication-competent herpes simplex virus combination induces local and systemic antitumor activity J Immunol 1998 160: 4457–4464

    CAS  PubMed  Google Scholar 

  61. Toda M, Rabkin SD, Martuza RL . Intratumoral inoculation of a replication-competent herpes simplex virus, G207, induces an antitumor immune response Proc Am Assoc Cancer Res 1997 38: 1176

    Google Scholar 

  62. Nishiyama Y, Yamada Y, Kurachi R, Daikoku T . Construction of a US3 lacZ insertion mutant of herpes simplex virus type 2 and characterization of its phenotype in vitro and in vivo Virology 1992 190: 256–268

    Article  CAS  PubMed  Google Scholar 

  63. Kusne S et al. Herpes simplex virus hepatitis after solid organ transplantation in adults J Infect Dis 1991 163: 1001–1007

    Article  CAS  PubMed  Google Scholar 

  64. Kaufman B et al. Herpes simplex virus hepatitis: case report and review Clin Infect Dis 1997 24: 334–338

    Article  CAS  PubMed  Google Scholar 

  65. DeLuca NA, Schaffer PA . Activities of herpes simplex virus type 1 (HSV-1) ICP4 genes specifying nonsense peptides Nucleic Acids Res 1987 15: 4491–4511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Osborne CK, Hobbs K, Clark GM . Effect of estrogens and anti-estrogens on growth of human breast cancer cells in athymic nude mice Cancer Res 1985 45: 584–590

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miyatake, SI., Tani, S., Feigenbaum, F. et al. Hepatoma-specific antitumor activity of an albumin enhancer/promoter regulated herpes simplex virus in vivo. Gene Ther 6, 564–572 (1999). https://doi.org/10.1038/sj.gt.3300861

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3300861

Keywords

This article is cited by

Search

Quick links