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:

An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer

Cancer Gene Therapy volume 13, pages 13–20 (2006)Cite this article

Abstract

The use of conditionally replicating adenoviruses offers an attractive complementary treatment strategy for localized prostate cancer. We have produced a replicating adenovirus, Ad[I/PPT-E1A], where E1A gene expression is controlled by a recombinant regulatory sequence designated PPT. The PPT sequence comprises a PSA enhancer, a PSMA enhancer and a T-cell receptor γ-chain alternate reading frame protein promoter, and it is shielded from transcriptional interference from adenoviral backbone sequences by an H19 insulator. Ad[I/PPT-E1A] yields prostate-specific E1A protein expression, viral replication and cytolysis in vitro. Furthermore, Ad[I/PPT-E1A] considerably regresses the growth of subcutaneous LNCaP prostate cancer tumors in nude mice. Importantly, the viral replication and cytolytic effect of Ad[I/PPT-E1A] are independent of the testosterone levels in the prostate cancer cells. This may be beneficial in a clinical setting since many prostate cancer patients are treated with androgen withdrawal. In conclusion, Ad[I/PPT-E1A] may prove to be useful in the treatment of localized prostate cancer.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Foley R, Lawler M, Hollywood D . Gene-based therapy in prostate cancer. Lancet Oncol 2004; 5: 469–479.

    Article  CAS  PubMed  Google Scholar 

  2. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E et al. Cancer statistics, 2004. CA Cancer J Clin 2004; 54: 8–29.

    Article  PubMed  Google Scholar 

  3. Jani AB, Hellman S . Early prostate cancer: clinical decision-making. Lancet 2003; 361: 1045–1053.

    Article  PubMed  Google Scholar 

  4. Scattoni V, Montorsi F, Picchio M, Roscigno M, Salonia A, Rtgatti P et al. Diagnosis of local recurrence after radical prostatectomy. BJU Int 2004; 93: 680–688.

    Article  CAS  PubMed  Google Scholar 

  5. Alemany R, Balague C, Curiel DT . Replicative adenoviruses for cancer therapy. Nat Biotechnol 2000; 18: 723–727.

    Article  CAS  PubMed  Google Scholar 

  6. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–376.

    Article  CAS  PubMed  Google Scholar 

  7. Rothmann T, Hengstermann A, Whitaker NJ, Scheffner M, zur Hausen H . Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells. J Virol 1998; 72: 9470–9478.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ries SJ, Brandts CH, Chung AS, Biederer CH, Hann BC, Lipner EM et al. Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015). Nat Med 2000; 6: 1128–1133.

    Article  CAS  PubMed  Google Scholar 

  9. Nemunaitis J, Cunningham C, Buchanan A, Blackburn A, Edelman G, Maples P et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Therapy 2001; 8: 746–759.

    Article  CAS  PubMed  Google Scholar 

  10. Nemunaitis J, Ganly I, Khuri F, Arseneau J, Kuhn J, McCarty T et al. Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial. Cancer Res 2000; 60: 6359–6366.

    CAS  PubMed  Google Scholar 

  11. Freytag SO, Khil M, Stricker H, Peabody J, Menon M, DePeralta-Venturina M et al. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 2002; 62: 4968–4976.

    CAS  PubMed  Google Scholar 

  12. Freytag SO, Stricker H, Pegg J, Paielli D, Pradhan DG, Peabody J et al. Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Cancer Res 2003; 63: 7497–7506.

    CAS  PubMed  Google Scholar 

  13. Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene 2000; 19: 2–12.

    Article  CAS  PubMed  Google Scholar 

  14. Huang TG, Savontaus MJ, Shinozaki K, Sauter BV, Woo SL . Telomerase-dependent oncolytic adenovirus for cancer treatment. Gene Therapy 2003; 10: 1241–1247.

    Article  CAS  PubMed  Google Scholar 

  15. Shirakawa T, Hamada K, Zhang Z, Okada H, Tagawa M, Kamidono S et al. A cox-2 promoter-based replication-selective adenoviral vector to target the cox-2-expressing human bladder cancer cells. Clin Cancer Res 2004; 10: 4342–4348.

    Article  CAS  PubMed  Google Scholar 

  16. Maemondo M, Saijo Y, Narumi K, Kikuchi T, Usui K, Tazawa R et al. Gene therapy with secretory leukoprotease inhibitor promoter-controlled replication-competent adenovirus for non-small cell lung cancer. Cancer Res 2004; 64: 4611–4620.

    Article  CAS  PubMed  Google Scholar 

  17. Hallenbeck PL, Chang YN, Hay C, Golightly D, Stewart D, Lin J et al. A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma. Hum Gene Ther 1999; 10: 1721–1733.

    Article  CAS  PubMed  Google Scholar 

  18. Yu DC, Sakamoto GT, Henderson DR . Identification of the transcriptional regulatory sequences of human kallikrein 2 and their use in the construction of calydon virus 764, an attenuated replication competent adenovirus for prostate cancer therapy. Cancer Res 1999; 59: 1498–1504.

    CAS  PubMed  Google Scholar 

  19. DeWeese TL, van der Poel H, Li S, Mikhak B, Drew R, Goemann M et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res 2001; 61: 7464–7472.

    CAS  PubMed  Google Scholar 

  20. Cheng WS, Giandomenico V, Pastan I, Essand M . Characterization of the androgen-regulated prostate-specific T cell receptor gamma-chain alternate reading frame protein (TARP) promoter. Endocrinology 2003; 144: 3433–3440.

    Article  CAS  PubMed  Google Scholar 

  21. Cheng WS, Kraaij R, Nilsson B, Van Der Weel L, De Ridder CM, Totterman TH et al. A novel TARP-promoter-based adenovirus against hormone-dependent and hormone-refractory prostate cancer. Mol Ther 2004; 10: 355–364.

    Article  CAS  PubMed  Google Scholar 

  22. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kanduri C, Holmgren C, Pilartz M, Franklin G, Kanduri M, Liu L et al. The 5′ flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication. Curr Biol 2000; 10: 449–457.

    Article  CAS  PubMed  Google Scholar 

  24. Yu W, Ginjala V, Pant V, Chemukhin I, Whitehead J, Docquier F et al. Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nat Genet 2004; 36: 1105–1110.

    Article  CAS  PubMed  Google Scholar 

  25. Nettelbeck DM, Rivera AA, Balague C, Alemany R, Curiel DT . Novel oncolytic adenoviruses targeted to melanoma: specific viral replication and cytolysis by expression of E1A mutants from the tyrosinase enhancer/promoter. Cancer Res 2002; 62: 4663–4670.

    CAS  PubMed  Google Scholar 

  26. Peter I, Graf C, Dummer R, Schaffner W, Greber UF, Hemmi S . A novel attenuated replication-competent adenovirus for melanoma therapy. Gene Therapy 2003; 10: 530–539.

    Article  CAS  PubMed  Google Scholar 

  27. Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR . 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 

  28. Yu DC, Chen Y, Seng M, Dilley J, Henderson DR . The addition of adenovirus type 5 region E3 enables calydon virus 787 to eliminate distant prostate tumor xenografts. Cancer Res 1999; 59: 4200–4203.

    CAS  PubMed  Google Scholar 

  29. Lee SJ, Zhang Y, Lee SD, Jung C, Li X, Kim HS et al. Targeting prostate cancer with conditionally replicative adenovirus using PSMA enhancer. Mol Ther 2004; 10: 1051–1058.

    Article  CAS  PubMed  Google Scholar 

  30. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000; 6: 879–885.

    Article  CAS  PubMed  Google Scholar 

  31. Nanda D, Vogels R, Havenga M, Avezaat CJ, Bout A, Smitt PS . Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase. Cancer Res 2001; 61: 8743–8750.

    CAS  PubMed  Google Scholar 

  32. Sova P, Ren XW, Ni S, Bernt KM, Mi J, Kiviat N et al. A tumor-targeted and conditionally replicating oncolytic adenovirus vector expressing TRAIL for treatment of liver metastases. Mol Ther 2004; 9: 496–509.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang Q, Nie M, Sham J, Su C, Xue H, Chua D et al. Effective gene-viral therapy for telomerase-positive cancers by selective replicative-competent adenovirus combining with endostatin gene. Cancer Res 2004; 64: 5390–5397.

    Article  CAS  PubMed  Google Scholar 

  34. Doronin K, Toth K, Kuppuswamy M, Krajcsi P, Tollefson AE, Wold WS . Overexpression of the ADP (E3-11.6K) protein increases cell lysis and spread of adenovirus. Virology 2003; 305: 378–387.

    Article  CAS  PubMed  Google Scholar 

  35. Lee CT, Park KH, Yanagisawa K, Adachi Y, Ohm JE, Nadaf S et al. Combination therapy with conditionally replicating adenovirus and replication defective adenovirus. Cancer Res 2004; 64: 6660–6665.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Valeria Giandomenico for technical advices and fruitful discussions. This work was supported by the Swedish Cancer Society (Grant 4419-B03-04XBB) and the European Community on behalf of the Prostate Cancer: Initiative for Gene Therapy group (Grant QLK6-CT-2000-00271).

Author information

Authors and Affiliations

  1. Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    W-S Cheng, H Dzojic, B Nilsson, T H Tötterman & M Essand

Authors
  1. W-S Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Dzojic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T H Tötterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Essand
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Essand.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, WS., Dzojic, H., Nilsson, B. et al. An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer. Cancer Gene Ther 13, 13–20 (2006). https://doi.org/10.1038/sj.cgt.7700881

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700881

Keywords

This article is cited by

Search

Advanced search

Quick links