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Oncolytic herpes viral therapy is effective in the treatment of hepatocellular carcinoma cell lines

  • Published:
Journal of Gastrointestinal Surgery

Abstract

The rising incidence of hepatocellular carcinoma (HCC) in western countries, along with the poor prognosis offered by present-day treatment modalities, makes novel therapies for this disease necessary. Oncolytic herpes simplex viruses (HSV) are replication-competent viruses that are highly effective in the treatment of a wide variety of experimental models of human malignancies. This study seeks to investigate the effectiveness of oncolytic herpes viruses in the treatment of primary HCC cell lines. Sixteen commercially available human HCC cell lines were studied. G207 is an attenuated, replication-competent, oncolytic HSV engineered to selectively replicate within cancer cells. Cell lines were tested for viral sensitivity to G207 and their ability to support viral replication using standard cytotoxicity and viral replication assays. Eleven of 16 cell lines were moderately to highly sensitive to G207 viral oncolysis. HCC cell lines additionally demonstrated the ability to support viral replication in vitro with as high as 800-fold amplification of the administered viral dose observed. G207 is cytotoxic to, and efficiently replicates within, HCC cell lines in vitro. From these data, we suggest that oncolytic HSV therapy may have a role in the treatment of HCC, and in vivo studies are warranted.

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References

  1. Staib F, Hussain SP, Hofseth LJ, Wang XW, Harris CC. Tp53 and liver carcinogenesis. Hum Mutat 2003;21:201–216.

    Article  PubMed  CAS  Google Scholar 

  2. Wang XW, Hussain SP, Huo TI, et al. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology 2002; 181-182:43–47.

    Article  PubMed  CAS  Google Scholar 

  3. Okuda K. Hepatocellular carcinoma. J Hepatol 2000;32:225–237.

    Article  PubMed  CAS  Google Scholar 

  4. American Cancer Society. Cancer Statistics Presentation 2004. American Cancer Society, 2004. Website http://www. cancer.org/docroot/pro/content/pro_1_1_cancer_statistics_ 2004_presentation.asp. Last accessed 14 Feb 2006.

  5. Toda M, Rabkin SD, Martuza RL. Treatment of human breast cancer in a brain metastatic model by G207, a replication-competent multimutated herpes simplex virus 1. Hum Gene Ther 1998;9:2177–2185.

    Article  PubMed  CAS  Google Scholar 

  6. Todo T, Rabkin SD, Chahlavi A, Martuza RL. Corticosteroid administration does not affect viral oncolytic activity, but inhibits antitumor immunity in replication-competent herpes simplex virus tumor therapy. Hum Gene Ther 1999; 10:2869–2878.

    Article  PubMed  CAS  Google Scholar 

  7. Chahlavi A, Todo T, Martuza RL, Rabkin SD. Replicationcompetent herpes simplex virus vector G207 and cisplatin combination therapy for head and neck squamous cell carcinoma. Neoplasia 1999;1:162–169.

    Article  PubMed  CAS  Google Scholar 

  8. Coukos G, Makrigiannakis A, Montas S, et al. Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not normal mesothelium and is suitable for intraperitoneal oncolytic therapy. Cancer Gene Ther 2000;7:275–283.

    Article  PubMed  CAS  Google Scholar 

  9. Oyama M, Ohigashi T, Hoshi M, et al. Intravesical and intravenous therapy of human bladder cancer by the herpes vector G207. Hum Gene Ther 2000;11:1683–1693.

    Article  PubMed  CAS  Google Scholar 

  10. Cozzi P, Burke PB, Bhargava A, et al. Oncolytic viral gene therapy for prostate cancer using two attenuated, replication competent, genetically-engineered herpes simplex viruses. Prostate 2002;53:95–100.

    Article  PubMed  CAS  Google Scholar 

  11. Stanziale SF, Fong Y. Novel approaches to cancer therapy using oncolytic viruses. Curr Mol Med 2003;3:61–71.

    Article  PubMed  CAS  Google Scholar 

  12. Ebright MI, Zager JS, Malhotra S, et al. Replication-competent herpes virus NV1020 as direct treatment of pleural cancer in a rat model. J Thorac Cardiovasc Surg 2002;124:123–129.

    Article  PubMed  Google Scholar 

  13. Bennett JJ, Malhotra S, Wong RJ, et al. Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer. Ann Surgery 2001;233:819–826.

    Article  CAS  Google Scholar 

  14. Bennett JJ, Kooby DA, Delman K, et al. Antitumor efficacy of regional oncolytic viral therapy for peritoneally disseminated cancer. J Mol Med 2000;78:166–174.

    Article  PubMed  CAS  Google Scholar 

  15. Carew JF, Kooby DA, Halterman MW, Federoff HJ, Fong Y. Selective infection and cytolysis of human head and neck squamous cell carcinoma with sparing of normal mucosa by a cytotoxic herpes simplex virus type 1 (G207). Hum Gene Ther 1999;10:1599–1606.

    Article  PubMed  CAS  Google Scholar 

  16. Cozzi PJ, Malhotra S, McAuliffe P, et al. Intravesical oncolytic viral therapy using attenuated, replication-competent herpes simplex viruses G207 and NV1020 is effective in the treatment of bladder cancer in an orthotopic syngeneic model. FASEB J 2001;15:1306–1308.

    PubMed  CAS  Google Scholar 

  17. 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.

    PubMed  CAS  Google Scholar 

  18. Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med 1995;1:938–943.

    Article  PubMed  CAS  Google Scholar 

  19. Chou J, Kern ER, Whitley RJ, Roizman B. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science 1990;250:1262–1266.

    Article  PubMed  CAS  Google Scholar 

  20. Whitley RJ, Kern ER, Chatterjee S, Chou J, Roizman B. Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models. J Clin Invest 1993;91:2837–2843.

    Article  PubMed  CAS  Google Scholar 

  21. Carroll NM, Chiocca EA, Takahashi K, Tanabe KK. Enhancement of gene therapy specificity for diffuse colon carcinoma liver metastases with recombinant herpes simplex virus. Ann Surg 1996;224:323–329.

    Article  PubMed  CAS  Google Scholar 

  22. Goldstein DJ, Weller SK. Factor(s) present in herpes simplex virus type 1-infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: Characterization of an ICP6 deletion mutant. Virology 1988;166:41–51.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  24. Decker T, Lohmann-Matthes ML. A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity. J Immunol Methods 1988; 115:61–69.

    Article  PubMed  CAS  Google Scholar 

  25. Korzeniewski C, Callewaert DM. An enzyme-release assay for natural cytotoxicity. J Immunol Methods 1983;64:313–320.

    Article  PubMed  CAS  Google Scholar 

  26. Weidmann E, Brieger J, Jahn B, Hoelzer D, Bergmann L, Mitrou PS. Lactate dehydrogenase-release assay: A reliable, nonradioactive technique for analysis of cytotoxic lymphocytemediated lytic activity against blasts from acute myelocytic leukemia. Ann Hematol 1995;70:153–158.

    Article  PubMed  CAS  Google Scholar 

  27. Park JG, Lee SK, Hong IG, et al. MDR1 gene expression: Its effect on drug resistance to doxorubicin in human hepatocellular carcinoma cell lines. J Natl Cancer Inst 1994;86:700–705.

    Article  PubMed  CAS  Google Scholar 

  28. Fogh J, Fogh JM, Orfeo T. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst 1977;59:221–226.

    PubMed  CAS  Google Scholar 

  29. Kang MS, Lee HJ, Lee JH, et al. Mutation of p53 gene in hepatocellular carcinoma cell lines with HBX DNA. Int J Cancer 1996;67:898–902.

    Article  PubMed  CAS  Google Scholar 

  30. Kim SO, Park JG, Lee YI. Increased expression of the insulin-like growth factor I (IGF-I) receptor gene in hepatocellular carcinoma cell lines: Implications of IGF-I receptor gene activation by hepatitis B virus 3 gene product. Cancer Res 1996;56:3831–3836.

    PubMed  CAS  Google Scholar 

  31. Park JG, Lee JH, Kang MS, et al. Characterization of cell lines established from human hepatocellular carcinoma. Int J Cancer 1995;62:276–282.

    Article  PubMed  CAS  Google Scholar 

  32. Alexander JJ, Bey EM, Geddes EW, Lecatsas G. Establishment of a continuously growing cell line from primary carcinoma of the liver. S Afr Med J 1976;50:2124–2228.

    PubMed  CAS  Google Scholar 

  33. Gilligan A, Bushmeyer S, Knowles BB. Variation in EGFinduced EGF receptor downregulation in human hepatoma-derived cell lines expressing different amounts of EGF receptor. Exp Cell Res 1992;200:235–241.

    Article  PubMed  CAS  Google Scholar 

  34. Macnab GM, Urbanowicz JM, Geddes EW, Kew MC. Hepatitis-B surface antigen and antibody in Bantu patients with primary hepatocellular cancer. Br J Cancer 1976;33:544–548.

    Article  PubMed  CAS  Google Scholar 

  35. Kawai HF, Kaneko S, Honda M, Shirota Y, Kobayashi K. Alpha-fetoprotein-producing hepatoma cell lines share common expression profiles of genes in various categories demonstrated by cDNA microarray analysis. Hepatology 2001; 33:676–691.

    Article  PubMed  CAS  Google Scholar 

  36. Heffelfinger SC, Hawkins HH, Barrish J, Taylor L, Darlington GJ. SK HEP-1: A human cell line of endothelial origin. In Vitro Cell Dev Biol 1992;28A:136–142.

    Article  PubMed  CAS  Google Scholar 

  37. Gucev ZS, Oh Y, Kelley KM, Labarta JI, Vorwerk P, Rosenfeld RG. Evidence for insulin-like growth factor (IGF)-independent transcriptional regulation of IGF binding protein-3 by growth hormone in SKHEP-1 human hepatocarcinoma cells. Endocrinology 1997;138:1464–1470.

    Article  PubMed  CAS  Google Scholar 

  38. Turner BM, Turner VS. Secretion of alpha 1-antitrypsin by an established human hepatoma cell line and by human/ mouse hybrids. Somatic Cell Genet 1980;6:1–14.

    Article  PubMed  CAS  Google Scholar 

  39. ATCC. American Type Culture Collection. ATCC. 2004. 2004. Website www.atcc.org. Last accessed 14 Feb 2006.

  40. Sharkey FE, Fogh J. Metastasis of human tumors in athymic nude mice. Int J Cancer 1979;24:733–738.

    Article  PubMed  CAS  Google Scholar 

  41. KCLB. Korean Cell Line Bank. KCLB. 2005. 2004. Website http://cellbank.snu.ac.kr/ENG/default.htm. Last accessed 14 Feb 2006.

  42. Pisani P, Bray F, Parkin DM. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int J Cancer 2002;97:72–81.

    Article  PubMed  CAS  Google Scholar 

  43. Parkin DM, Bray FI, Devesa SS. Cancer burden in the Year 2000. The global picture. Eur J Cancer 2001;37(Suppl 8):S4-S66.

    Article  PubMed  Google Scholar 

  44. El Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750.

    Article  PubMed  CAS  Google Scholar 

  45. Department of Health and Human Services, Centers for Disease Control and Prevention, National Cancer Institutes. US Cancer Statistics Working Group. United States Cancer Statistics: 2000 Incidence. pp 50–77. 2003. Atlanta, GA.

  46. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999;229:790–799.

    Article  PubMed  CAS  Google Scholar 

  47. Hamazoe R, Hirooka Y, Ohtani S, Katoh T, Kaibara N. Intraoperative microwave tissue coagulation as treatment for patients with nonresectable hepatocellular carcinoma. Cancer 1995;75:794–800.

    Article  PubMed  CAS  Google Scholar 

  48. Fong Y. A promising technique for liver cancer? Cancer J Sci Am 1999;5:339–340.

    PubMed  CAS  Google Scholar 

  49. Giorgio A, Ferraioli G. Radiofrequency thermal ablation versus percutaneous ethanol injection for small hepatocellular carcinoma. Radiology 2004;230:886–887.

    Article  PubMed  Google Scholar 

  50. Zuber-Jerger I, Geissler M, Spangenberg HC, Mohr L, Weizsacker F, Blum HE. Local ablation of malignant lesions of the liver -potential applications and limitations of the different methods. Z Gastroenterol 2004;42:31–38.

    Article  PubMed  CAS  Google Scholar 

  51. Segawa T, Tsuchiya R, Furui J, Izawa K, Tsunoda T, Kanematsu T. Operative results in 143 patients with hepatocellular carcinoma. World J Surg 1993;17:663–667.

    Article  PubMed  CAS  Google Scholar 

  52. Lau WY, Arnold M, Guo SK, Li AK. Microwave tissue coagulator in liver resection for cirrhotic patients. Aust N Z J Surg 1992;62:576–581.

    Article  PubMed  CAS  Google Scholar 

  53. Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: Randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection. Radiology 2003;228:235–240.

    Article  PubMed  Google Scholar 

  54. Kramm CM, Chase M, Herrlinger U, et al. Therapeutic efficiency and safety of a second-generation replicationconditional HSV1 vector for brain tumor gene therapy. Hum Gene Ther 1997;8:2057–2068.

    Article  PubMed  CAS  Google Scholar 

  55. Delman KA, Zager JS, Bhargava A, et al. Effect of murine liver cell proliferation on herpes viral behavior: Implications for oncolytic viral therapy. Hepatology 2004;39:1525–1532.

    Article  PubMed  CAS  Google Scholar 

  56. Fong Y, Kemeny N, Jarnagin W, et al. Phase 1 study of a replication-competent herpes simplex oncolytic virus for treatment of hepatic colorectal metastases. Proc Am Soc Clin Oncol 2002;21:8a.

    Google Scholar 

  57. Lin E, Nemunaitis J. Oncolytic viral therapies. Cancer Gene Ther 2004;11:643–664.

    Article  PubMed  CAS  Google Scholar 

  58. Markert JM, Medlock MD, Rabkin SD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: Results of a phase I trial. Gene Ther 2000;7:867–874.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Yuman Fong M.D..

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Supported by grants R01CA75461 and R01CA72632 from the National Institutes of Health, and by grant MBC-99366 from the American Cancer Society (Yuman Fong).

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Song, TJ., Eisenberg, D.P., Adusumilli, P.S. et al. Oncolytic herpes viral therapy is effective in the treatment of hepatocellular carcinoma cell lines. Journal of Gastrointestinal Surgery 10, 532–542 (2006). https://doi.org/10.1016/j.gassur.2005.08.036

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