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.

  • Original Article
  • Published:

Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positive and -negative nasopharyngeal carcinoma

Cancer Gene Therapy volume 8, pages 352–360 (2001)Cite this article

Abstract

We have previously shown that the introduction of human recombinant wild-type p53 mediated by an adenoviral vector (Ad5CMV-p53), either alone or delivered in combination with ionizing radiation, was cytotoxic to two nasopharyngeal carcinoma (NPC) cell lines. To further explore the potential therapeutic role for gene therapy, the combination of Ad5CMV-p53 and cisplatin was examined in two NPC cell lines, CNE-1 and C666-1. The C666-1 cells are particularly relevant because they express Epstein-Barr virus latent gene products analogous to human NPC in situ. Cells were infected with 5 pfu/cell of Ad5CMV-p53 or Ad5CMV-β-gal, followed by exposure to increasing doses of cisplatin. Clonogenic and MTT assays were used to assess the sensitivity of cells to these treatments, and apoptosis was also quantified. The combination of Ad5CMV-p53 and cisplatin resulted in approximately 25% greater cytotoxicity compared to that observed with cisplatin alone in either cell line. Apoptosis was induced in approximately 50% of cells following administration of both Ad5CMV-p53 and cisplatin, but was induced in considerably fewer cells following either treatment alone. The two modalities appeared to interact in an additive manner. Ad5CMV-p53 gene therapy resulted in the expression of biologically active p53 protein, shown by induction of p21WAF1/CIP1. Cisplatin treatment showed little effect on either p53 or p21WAF1/CIP1 expression. Therefore, both p53 gene therapy and cisplatin chemotherapy demonstrated cytotoxicity mediated by apoptosis despite the presence of EBV gene products in the C666-1 cells, but it appears that the two modalities induce cytotoxicity by independent pathways. Cancer Gene Therapy (2001) 8, 352–360

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Allday MJ, Sinclair A, Parker G, Crawford DH, Farrell PJ . Epstein-Barr virus efficiently immortalizes human B cells without neutralizing the function of p53 EMBO J. 1995 14: 1382–1391

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Al-Sarraf M, LeBlanc M, Giri PG, et al . Chemoradiotherapyversus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup Study 0099 J Clin Oncol 1998 16: 1310–1317

    CAS  PubMed  Google Scholar 

  3. Altun M, Fandi A, Dupuis O, Cvitkovic E, Krajina Z, Eschwege F . Undifferentiated nasopharyngeal cancer (UCNT): current diagnostic and therapeutic aspects Int J Radiat Oncol Biol Phys 1995 32: 859–877

    CAS  PubMed  Google Scholar 

  4. Burger H, Nooter K, Boersma AW, Kortland CJ, Stoter G . Expression of p53, Bcl-2, and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines Br J Cancer 1998 77: 1562–1567

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen X, Ko LJ, Jayaraman L, Prives C . p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells Genes Dev 1996 10: 2438–2451

    CAS  PubMed  Google Scholar 

  6. Cheung ST, Huang DP, Hui AB, et al . Nasopharyngeal carcinoma cell line (C666-1) consistently harboring Epstein-Barr virus Int J Cancer 1999 83: 121–126

    CAS  PubMed  Google Scholar 

  7. Cirielli C, Riccioni T, Yang C, et al . Adenovirus-mediated gene transfer of wild-type p53 results in melanoma cell apoptosisin vitro andin vivo Int J Cancer 1995 63: 673–679

    CAS  PubMed  Google Scholar 

  8. Clayman GL, El-Naggar AK, Roth JA, et al . In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma Cancer Res 1995 55: 1–6

    CAS  PubMed  Google Scholar 

  9. Codd JD, Salisbury JR, Packham G, Nicholson LJ . A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma J Pathol 1999 187: 549–555

    CAS  PubMed  Google Scholar 

  10. Eastman A . Activation of programmed cell death by anticancer agents: cisplatin as a model system Cancer Cells 1990 2: 275–280

    CAS  PubMed  Google Scholar 

  11. Effert P, McCoy R, Abdel-Hamid M, et al . Alterations of thep53 gene in nasopharyngeal carcinoma J Virol 1992 66: 3768–3775

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Fahraeus R, Rymo L, Rhim JS, Klein G . Morphological transformation of human keratinocytes expressing the LMP gene of Epstein-Barr virus Nature 1990 345: 447–449

    CAS  PubMed  Google Scholar 

  13. Fries KL, Miller WE, Raab-Traub N . Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of theA20 gene J Virol 1996 70: 8653–8659

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fujiwara T, Grimm EA, Mukhopadhyay T, Zhang WW, Owen-Schaub LB, Roth JA . Induction of chemosensitivity in human lung cancer cellsin vivo by adenovirus-mediated transfer of the wild-type p53 gene Cancer Res 1994 54: 2287–2291

    CAS  PubMed  Google Scholar 

  15. Hamada K, Alemany R, Zhang WW, et al . Adenovirus-mediated transfer of a wild-type p53 gene and induction of apoptosis in cervical cancer Cancer Res 1996 56: 3047–3054

    CAS  PubMed  Google Scholar 

  16. Hui AB, Cheung ST, Fong Y, Lo KW, Huang DP . Characterization of a new EBV-associated nasopharyngeal carcinoma cell line Cancer Genet Cytogenet 1998 101: 83–88

    CAS  PubMed  Google Scholar 

  17. Kanamori Y, Kigawa J, Minagawa Y, et al . A newly developed adenovirus-mediated transfer of a wild-type p53 gene increases sensitivity tocis-diamminedichloroplatinum(II) in p53- deleted ovarian cancer cells Eur J Cancer 1998 34: 1802–1806

    CAS  PubMed  Google Scholar 

  18. Katayose D, Gudas J, Nguyen H, Srivastava S, Cowan KH, Seth P . Cytotoxic effects of adenovirus-mediated wild-type p53 protein expression in normal and tumor mammary epithelial cells Clin Cancer Res 1995 1: 889–897

    CAS  PubMed  Google Scholar 

  19. Kawanishi M . Expression of Epstein-Barr virus latent membrane protein 1 protects Jurkat T cells from apoptosis induced by serum deprivation Virology 1997 228: 244–250

    CAS  PubMed  Google Scholar 

  20. Knox PG, Li Q-X, Rickinson AB, Young LS . In vitro production of stable Epstein-Barr virus–positive epithelial cell clones which resemble the virus: cell interaction observed in nasopharyngeal carcinoma Virology 1996 215: 40–50

    CAS  PubMed  Google Scholar 

  21. Li JH, Lax SA, Kim J, Klamut H, Liu FF . The effects of combining ionizing radiation and adenoviral p53 therapy in nasopharyngeal carcinoma Int J Radiat Oncol Biol Phys 1999 43: 607–616

    CAS  PubMed  Google Scholar 

  22. Li JH, Li P, Klamut H, Liu FF . Cytotoxic effects of Ad5CMV-p53 expression in two human nasopharyngeal carcinoma cell lines Clin Cancer Res 1997 3: 507–514

    CAS  PubMed  Google Scholar 

  23. Li J-H, Huang D, Sun B-F, et al . The efficacy of ionizing radiation combined with adenoviral p53 therapy in EBV-positive nasopharyngeal carcinoma Int J Cancer 2000 7: 606–610

    Google Scholar 

  24. Liebowitz D . Nasopharyngeal carcinoma: the Epstein-Barr virus association Semin Oncol 1994 21: 376–381

    CAS  PubMed  Google Scholar 

  25. Lo K-W, Mok C-H, Huang DP, et al . p53 mutation in human nasopharyngeal carcinomas Anticancer Res 1992 12: 1957–1964

    CAS  PubMed  Google Scholar 

  26. Matsubara H, Kimura M, Sugaya M, et al . Expression of wild-type p53 gene confers increased sensitivity to radiation and chemotherapeutic agents in human esophageal carcinoma cells Int J Oncol 1999 14: 1081–1085

    CAS  PubMed  Google Scholar 

  27. Moorthy RK, Thorley-Lawson DA . All three domains of the Epstein-Barr virus–encoded latent membrane protein LMP-1 are required for transformation of rat-1 fibroblasts J Virol 1993 67: 1638–1646

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mujoo K, Maneval DC, Anderson SC, Gutterman JU . Adenoviral-mediated p53 tumor-suppressor gene therapy of human ovarian carcinoma Oncogene 1996 12: 1617–1623

    CAS  PubMed  Google Scholar 

  29. Niedobitek G, Agathanggelou A, Nicholls J . Epstein-Barr virus infection and the pathogenesis of nasopharyngeal carcinoma: viral gene expression, tumor cell phenotype, and the role of the lymphoid stroma Semin Cancer Biol 1996 7: 165–174

    CAS  PubMed  Google Scholar 

  30. Ogawa N, Fujiwara T, Kagawa S, et al . Novel combination therapy for human colon cancer with adenovirus- mediated wild-type p53 gene transfer and DNA-damaging chemotherapeutic agent Int J Cancer 1997 73: 367–370

    CAS  PubMed  Google Scholar 

  31. Okan I, Wang Y, Chen F, et al . The EBV-encoded LMP1 protein inhibits p53-triggered apoptosis but not growth arrest Oncogene 1995 11: 1027–1031

    CAS  PubMed  Google Scholar 

  32. Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N . Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma [see comments] N Engl J Med 1995 333: 693–698

    CAS  PubMed  Google Scholar 

  33. Pirollo KF, Hao Z, Rait A, et al . p53-mediated sensitization of squamous cell carcinoma of the head and neck to radiotherapy Oncogene 1997 14: 1735–1746

    CAS  PubMed  Google Scholar 

  34. Raab-Traub N . Epstein-Barr virus and nasopharyngeal carcinoma Semin Cancer Biol 1992 3: 297–307

    CAS  PubMed  Google Scholar 

  35. Ramqvist T, Magnusson K, Wang Y, Szekeley L, Klein G . Wild-type p53 induces apoptosis in a Burkitt lymphoma (BL) line that carries mutant p53 Oncogene 1993 8: 1495–1500

    CAS  PubMed  Google Scholar 

  36. Roberts JJ, Thomson AJ . The mechanism of action of antitumor platinum compounds Prog Nucleic Acid Res Mol Biol 1979 22: 71–133

    CAS  PubMed  Google Scholar 

  37. Sato S, Kigawa J, Minagawa Y, et al . Chemosensitivity and p53-dependent apoptosis in epithelial ovarian carcinoma Cancer 1999 86: 1307–1313

    CAS  PubMed  Google Scholar 

  38. Show P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J . Induction of apoptosis by wild-type p53 in a human colon tumor–derived cell line Proc Natl Acad Sci USA 1992 89: 4495–4499

    Google Scholar 

  39. Sizhong Z, Xiukung G, Yi Z . Cytogenetic studies on an epithelial cell line derived from poorly differentiated nasopharyngeal carcinoma Int J Cancer 1983 31: 587–590

    CAS  PubMed  Google Scholar 

  40. Sorenson CM, Barry MA, Eastman A . Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin J Natl Cancer Inst 1990 82: 749–755

    CAS  PubMed  Google Scholar 

  41. Sorenson CM, Eastman A . Mechanism ofcis-diamminedichloroplatinum(II)–induced cytotoxicity: role of G2 arrest and DNA double-strand breaks Cancer Res 1988 48: 4484–4488

    CAS  PubMed  Google Scholar 

  42. Szekely L, Selivanova G, Magnusson KP, Klein G, Wiman KG . EBNA-5, an Epstein-Barr virus–encoded nuclear antigen, binds to the retinoblastoma and p53 proteins Proc Natl Acad Sci USA 1993 90: 5455–5459

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang D, Liebowitz D, Kieff E . An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells Cell 1985 43: 831–840

    CAS  PubMed  Google Scholar 

  44. Wu GS, El-Deiry WS . Apoptotic death of tumor cells correlates with chemosensitivity, independent of p53 or bcl-2 Clin Cancer Res 1996 2: 623–633

    CAS  PubMed  Google Scholar 

  45. Yang C, Cirielli C, Capogrossi MC, Passaniti A . Adenovirus-mediated wild-type p53 expression induces apoptosis and suppresses tumorigenesis of prostatic tumor cells Cancer Res 1995 55: 4210–4213

    CAS  PubMed  Google Scholar 

  46. Zeng Y . Establishment of an epithelioid cell line and a fusiform cell line from a patient with nasopharyngeal carcinoma Sci Sin 1978 21: 127

    Google Scholar 

  47. Zhang Q, Gutsch D, Kenney S . Functional and physical interaction between p53 and BZLF1: implications for Epstein-Barr virus latency Mol Cell Biol 1994 14: 1929–1938

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang WW, Alemany R, Wang J, Koch PE, Ordonez NG, Roth JA . Safety evaluation of Ad5CMV-p53in vitro andin vivo Hum Gene Ther 1995 6: 155–164

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by funds from the Medical Research Council of Canada.

Author information

Authors and Affiliations

  1. Department of Experimental Therapeutics, Princess Margaret Hospital/Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    Laura Weinrib, Jian-Hua Li, Jeffrey Donovan & Fei-Fei Liu

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Laura Weinrib, Jian-Hua Li, Jeffrey Donovan & Fei-Fei Liu

  3. Chinese University of Hong Kong, Shatin, Hong Kong, China

    Dolly Huang

  4. Department of Radiation Oncology, Princess Margaret Hospital/Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    Fei-Fei Liu

  5. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada

    Fei-Fei Liu

Authors
  1. Laura Weinrib
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian-Hua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dolly Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fei-Fei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fei-Fei Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weinrib, L., Li, JH., Donovan, J. et al. Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positive and -negative nasopharyngeal carcinoma. Cancer Gene Ther 8, 352–360 (2001). https://doi.org/10.1038/sj.cgt.7700319

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700319

Keywords

Search

Advanced search

Quick links