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Herpes simplex virus thymidine kinase gene transduction enhances tumor growth rate and cyclooxygenase-2 expression in murine colon cancer cells

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Abstract

Transduction of tumor cells with herpes simplex virus thymidine kinase (HSV-tk) gene and subsequent treatment with the prodrug ganciclovir (GCV) is the most common system utilized to date for “suicide” gene therapy of cancer. In the current report, we show that HSV-tk gene transduction enhances tumor growth rate of murine colon cancer cells, that are implanted subcutaneously in syngeneic mice, and enhances cyclooxygenase-2 (COX-2) protein expression and prostaglandin E2 (PGE2) release in vitro and in vivo. It is further shown that the observed phenomenon is related to the presence of the HSV-tk sequence insert in the retroviral vector used for HSV-tk gene delivery. Transduction of murine colon cancer cells with control vector, carrying the neomycin-resistance gene alone, failed to increase tumor growth rate and COX-2 protein expression or PGE2 production. On the contrary, it even decreased tumor growth, COX-2 protein expression and PGE2. The growth rate of HSV-tk-transduced murine tumors was significantly reduced by treatment with the selective COX-2 inhibitor nimesulide. Additionally, we demonstrate herein that both enhanced growth rate of HSV-tk-transduced murine tumors and increased levels of PGE2 in HSV-tk-transduced cells persist upon the development of GCV resistance. Taken together, these results provide a better understanding of the direct effect of HSV-tk gene transduction on tumor cell biology and target tumor development.

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References

  1. Moolten FL, Wells JM . Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst. 1990;82:297–300.

    Article  CAS  PubMed  Google Scholar 

  2. Moolten FL . Drug sensitivity (“suicide”) genes for selective cancer chemotherapy. Cancer Gene Ther. 1994;1:279–287.

    CAS  PubMed  Google Scholar 

  3. Ram Z, Culver KW, Oshiro EM, et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med. 1997;12: 1354–1361.

    Article  Google Scholar 

  4. Zwacka RM, Dunlop MG . Gene therapy for colon cancer. Hematol Oncol Clin North Am. 1998;12:595–615.

    Article  CAS  PubMed  Google Scholar 

  5. Matsubara H, Kawamura K, Sugaya M, et al. Differential efficacy of suicide gene therapy by herpes simplex virus-thymidine kinase gene reflects the status of p53 gene in human esophageal cancer cells. Anticancer Res. 1999;19: 4157–4160.

    CAS  PubMed  Google Scholar 

  6. Cho HS, Park YN, Lyu CJ, et al. Effects of retroviral-mediated herpes simplex virus thymidine kinase gene transfer to murine neuroblastoma cell lines in vitro and in vivo. Acta Oncol. 1999;38:1093–1097.

    Article  CAS  PubMed  Google Scholar 

  7. Wildner O . In situ use of suicide genes for therapy of brain tumors. Ann Med. 1999;31:421–429.

    Article  CAS  PubMed  Google Scholar 

  8. Moriuchi S, Krisky DM, Marconi PC, et al. HSV vector cytotoxicity is inversely correlated with effective TK/GCV suicide gene therapy of rat gliosarcoma. Gene Therapy. 2000;7:1483–1490.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang L, Wikenheiser KA, Whitsett JA . Limitations of retrovirus-mediated HSV-tk gene transfer to pulmonary adenocarcinoma cells in vitro and in vivo. Hum Gene Ther. 1997;8:563–574.

    Article  CAS  PubMed  Google Scholar 

  10. Garin MI, Garrett E, Tiberghien P, et al. Molecular mechanism for ganciclovir resistance in human T lymphocytes transduced with retroviral vectors carrying the herpes simplex virus thymidine kinase gene. Blood. 2001;97:122–129.

    Article  CAS  PubMed  Google Scholar 

  11. Needleman P, Turk J, Jakschik BA, et al. Arachidonic acid metabolism. Annu Rev Biochem. 1986;55:69–102.

    Article  CAS  PubMed  Google Scholar 

  12. O'Neill GP, Ford-Hutchinson AW . Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett. 1993;330:156–160.

    Article  CAS  PubMed  Google Scholar 

  13. Williams CS, DuBois RN . Prostaglandin endoperoxide synthase: why two isoforms? Am J Physiol. 1996;270: G393–G400.

    CAS  PubMed  Google Scholar 

  14. Birkle DL, Sanitato JJ, Kaufman HE, Bazan NG . Arachidonic acid metabolism to eicosanoids in herpes virus-infected rabbit cornea. Invest Ophthalmol Vis Sci. 1986;27:1443–1446.

    CAS  PubMed  Google Scholar 

  15. Heitman CR, Waite M, Kucera LS . Studies of phospholipase and cyclooxygenase activities in herpes simplex virus type 2-transformed rat cells. Carcinogenesis. 1989;10:2059–2065.

    Article  CAS  PubMed  Google Scholar 

  16. Murono S, Inoue H, Tanabe T, et al. Induction of cyclooxygenase-2 by Epstein-Barr virus latent membrane protein 1 is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells. Proc Natl Acad Sci USA. 2001;98:6905–6910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pereira CF, Boven LA, Middel J, et al. Induction of cyclooxygenase-2 expression during HIV-1-infected monocyte-derived macrophage and human brain microvascular endothelial cell interactions. J Leukoc Biol. 2000;68:423–428.

    CAS  PubMed  Google Scholar 

  18. Bagetta G, Corasaniti MT, Paoletti AM, et al. HIV-1 gp120-induced apoptosis in the rat neocortex involves enhanced expression of cyclo-oxygenase type 2 (COX-2). Biochem Biophys Res Commun. 1998;244:819–824.

    Article  CAS  PubMed  Google Scholar 

  19. Mori N, Inoue H, Yoshida T, et al. Constitutive expression of the cyclooxygenase-2 gene in T-cell lines infected with human T-cell leukemia virus type I. Int J Cancer. 2001;94:813–819.

    Article  CAS  PubMed  Google Scholar 

  20. Hirschowitz E, Hidalgo G, Doherty D . Induction of cyclo-oxygenase-2 in non-small cell lung cancer cells by infection with DeltaE1, DeltaE3 recombinant adenovirus vectors. Gene Therapy. 2002;9:81–84.

    Article  CAS  PubMed  Google Scholar 

  21. Wachsman M, Aurelian L, Burnett JW . The prophylactic use of cyclooxygenase inhibitors in recurrent herpes simplex infections. Br J Dermatol. 1990;123:375–380.

    Article  CAS  PubMed  Google Scholar 

  22. Smith WL . Prostanoid biosynthesis and mechanisms of action. Am J Physiol. 1992;263:F181–F191.

    CAS  PubMed  Google Scholar 

  23. Dannenberg AJ, Altorki NK, Boyle JO, et al. Cyclooxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol. 2001;2:544–551.

    Article  CAS  PubMed  Google Scholar 

  24. Subbaramaiah K, Dannenberg AJ . Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci. 2003;24:96–102.

    Article  CAS  PubMed  Google Scholar 

  25. Lupulescu A . Prostaglandins, their inhibitors and cancer. Prostaglandins Leukot Essent Fatty Acids. 1996;54:83–94.

    Article  CAS  PubMed  Google Scholar 

  26. Tsuji S, Tsujii M, Kawano S, Hori M . Cyclooxygenase-2 upregulation as a perigenetic change in carcinogenesis. J Exp Clin Cancer Res. 2001;20:117–129.

    CAS  PubMed  Google Scholar 

  27. Fujita T, Matsui M, Takaku K, et al. Size- and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas. Cancer Res. 1998;58:4823–4826.

    CAS  PubMed  Google Scholar 

  28. Ohno R, Yoshinaga K, Fujita T, et al. Depth of invasion parallels increased cyclooxygenase-2 levels in patients with gastric carcinoma. Cancer. 2001;91:1876–1881.

    Article  CAS  PubMed  Google Scholar 

  29. Taketo MM . Cyclooxygenase-2 inhibitors in tumorigenesis (II). J Natl Cancer Inst. 1998;21:1609–1620.

    Article  Google Scholar 

  30. Milas L, Kishi K, Hunter N, et al. Enhancement of tumor response to gamma-radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl Cancer Inst. 1999;91:1501–1504.

    Article  CAS  PubMed  Google Scholar 

  31. Chen Q, Shinohara N, Abe T, Watanabe T, Nonomura K, Koyanagi T . Significance of COX-2 expression in human renal cell carcinoma cell lines. Int J Cancer. 2004;108:825–832.

    Article  CAS  PubMed  Google Scholar 

  32. Tsujii M, Kawano S, DuBois RN . Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA. 1997;94:3336–3340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Leung WK, To KF, Go MY, et al. Cyclooxygenase-2 upregulates vascular endothelial growth factor expression and angiogenesis in human gastric carcinoma. Int J Oncol. 2003;23:1317–1322.

    CAS  PubMed  Google Scholar 

  34. Fujita H, Koshida K, Keller ET, et al. Cyclooxygenase-2 promotes prostate cancer progression. Prostate. 2002;53: 232–240.

    Article  CAS  PubMed  Google Scholar 

  35. Degr'eve B, De Clercq E, Balzarini J . Selection of HSV-1 TK gene-transfected murine mammary carcinoma cells resistant to (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and ganciclovir (GCV). Gene Therapy. 2000;7:1543–1552.

    Article  CAS  Google Scholar 

  36. Chou TC, Haball M . CalcuSyn for Windows, Multiple-Drug Dose-effect Analyzer and Manual. Cambridge, UK: Biosoft; (1996).

    Google Scholar 

  37. Agbaria R, Candotti F, Kelley JA, et al. Biosynthetic ganciclovir triphosphate: its isolation and characterization from ganciclovir-treated herpes simplex thymidine kinase-transduced murine cells. Biochem Biophys Res Commun. 2001;289:525–530.

    Article  CAS  PubMed  Google Scholar 

  38. Noy R, Ben-Zvi Z, Elezra M, et al. Pharmacokinetics and organ distribution of N-methanocarbathymidine, a novel thymidine analog, in mice bearing tumors transduced with the herpes simplex thymidine kinase gene. Cancer Chemother Pharmacol. 2002;50:360–366.

    Article  CAS  PubMed  Google Scholar 

  39. Danon A, Leibson V, Assouline G . Effects of aspirin, indomethacin, flufenamic acid and paracetamol on prostaglandin output from rat stomach and renal papilla in vitro and ex vivo. J Pharm Pharmacol. 1983;35:576–579.

    Article  CAS  PubMed  Google Scholar 

  40. D'Acquisto F, Iuvone T, Rombola L, et al. Involvement of NF-κB in the regulation of cyclooxygenase-2 protein expression in LPS-stimulated J774 macrophages. FEBS Lett. 1997;418:175–178.

    Article  CAS  PubMed  Google Scholar 

  41. Lowry OH, Roseborough NJ, Farr AL, Randall RJ . Protein measurement with folin phenol reagent. J Biol Chem. 1951;193:265–275.

    CAS  PubMed  Google Scholar 

  42. Bishop-Bailey D, Calatayud S, Warner TD, et al. Prostaglandins and the regulation of tumor growth. J Environ Pathol Toxicol Oncol. 2002;21:93–101.

    Article  CAS  PubMed  Google Scholar 

  43. Kawamori T, Rao CV, Seibert K, Reddy BS . Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res. 1998;58: 409–412.

    CAS  PubMed  Google Scholar 

  44. Sheng H, Shao J, Kirkland SC, et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest. 1997;99:2254–2259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Harris RE, Alshafie GA, Abou-Issa H, Seibert K . Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res. 2000;60:2101–2103.

    CAS  PubMed  Google Scholar 

  46. Zweifel BS, Davis TW, Ornberg RL, Masferrer JL . Direct evidence for a role of cyclooxygenase 2-derived prostaglandin E2 in human head and neck xenograft tumors. Cancer Res. 2002;62:6706–6711.

    CAS  PubMed  Google Scholar 

  47. Williams CS, Tsujii M, Reese J, et al. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest. 2000;105:1589–1594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pentland AP, Schoggins JW, Scott GA, et al. Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis. 1999;20:1939–1944.

    Article  CAS  PubMed  Google Scholar 

  49. Reddy BS, Hirose Y, Lubet R, et al. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res. 2000;60:293–297.

    CAS  PubMed  Google Scholar 

  50. Okajima E, Denda A, Ozono S, et al. Chemopreventive effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on the development of rat urinary bladder carcinomas initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine. Cancer Res. 1998;58:3028–3023.

  51. Denda A, Kitayama W, Murata A, et al. Increased expression of cyclooxygenase-2 protein during rat hepatocarcinogenesis caused by a choline-deficient, L-amino acid-defined diet and chemopreventive efficacy of a specific inhibitor, nimesulide. Carcinogenesis. 2002;23:245–256.

    Article  CAS  PubMed  Google Scholar 

  52. Smith ML, Hawcroft G, Hull MA . The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur J Cancer. 2000;36:664–674.

    Article  CAS  PubMed  Google Scholar 

  53. Tegeder I, Pfeilschifter J, Geisslinger G . Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J. 2001;15:2057–2072.

    Article  CAS  PubMed  Google Scholar 

  54. DuBois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J. 1998;12:1063–1073.

    Article  CAS  PubMed  Google Scholar 

  55. Appleby SB, Ristimaki A, Neilson K, Narko K, Hla T . Structure of the human cyclooxygenase-2 gene. Biochem J. 1994;302:723–727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by the ISRAEL SCIENCE FOUNDATION (Grant No 500/02).

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, POB 653, Beer-Sheva, 84105, Israel

    Alexander Konson, Tsipi Ben-Kasus, Abraham Danon, Gilad Rimon & Riad Agbaria

  2. Migal-Galilee Technology Center, Cancer Drug Discovery Program, POB 831, Kiryat Shmona, 11016, Israel

    Jamal A Mahajna

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  1. Alexander Konson
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  2. Tsipi Ben-Kasus
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  3. Jamal A Mahajna
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Correspondence to Riad Agbaria.

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Konson, A., Ben-Kasus, T., Mahajna, J. et al. Herpes simplex virus thymidine kinase gene transduction enhances tumor growth rate and cyclooxygenase-2 expression in murine colon cancer cells. Cancer Gene Ther 11, 830–840 (2004). https://doi.org/10.1038/sj.cgt.7700768

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  • DOI: https://doi.org/10.1038/sj.cgt.7700768

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