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.

Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer

Cancer Gene Therapy volume 10, pages 224–238 (2003)Cite this article

Abstract

A cohort study was designed to evaluate the efficiency of gene transfer and whether biological activity from the expressed therapeutic gene resulted after administration of a recombinant adenovirus containing the human wild-type p53 (p53wt) gene (rAd-p53 SCH 58500). The cohort study was conducted in five trial subjects with recurrent ovarian cancer. Each trial subject received multiple cycles of rAd-p53 SCH 58500, each cycle comprised of doses of 7.5 × 1013 particles on each of five consecutive days. Subjects were treated with rAd-p53 SCH 58500 alone during Cycle 1 and in combination with gemcitabine during the subsequent cycles. Both tumor biopsies and peritoneal aspirates were collected and evaluated for gene transfer and evidence of the biological activities of the expressed p53wt gene. Using quantitative PCR and RT-PCR, and in situ PCR, gene transfer and expression were documented in tumor biopsies (four of five patients) collected from Cycle 1. Furthermore, upregulation of p21/WAF1, bax and mdm-2, and downregulation of survivin were observed in these same tumor biopsy samples, suggesting that intraperitoneal administration of rAd-p53 SCH 58500 leads to detectable p53 biological activity in target tumor tissue. In addition, gene transfer and its expression were observed in cells obtained from peritoneal aspirates. These fluids were mainly comprised of polymorphonuclear neutrophils, indicating that successful gene transfer can be achieved by multiple cycle intraperitoneal administration of recombinant adenovirus.

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

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. Dummer R, Bergh J, Karlsson Y, et al. Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors. Cancer Gene Ther. 2000;7:1069–1076.

    Article  CAS  Google Scholar 

  2. Schuler M, Rochlitz C, Horowitz JA, et al. A phase I study of adenovirus mediated wild type p53 gene therapy in patients with advanced non-small cell lung cancer. Hum Gene Ther. 1998;15:1750–1758.

    Google Scholar 

  3. Schuler M, Herrmann R, De Greve JL, et al. Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multi-center phase II study. J Clin Oncol. 2001;19:1750–1758.

    Article  CAS  Google Scholar 

  4. Kuball J, Wen SF, Leissner J, et al. Successful adenovirus –mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation. J Clin Oncol. 2002;20:957–965.

    Article  CAS  Google Scholar 

  5. Ring E, Nonaka-Wong S, Horowitz JA, et al. Gene therapy of colorectal liver metastases using a recombinant adenovirus encoding wt p53 (SCH 58500) via hepatic artery infusion: a phase I study. Abstract. ASCO, 1998.

  6. Buller RE, Shahin MS, Horowitz J, et al. Long term follow-up of patients with recurrent ovarian cancer after Ad p53 gene replacement with SCH 58500. Cancer Gene Ther. 2002;9:567–572.

    Article  CAS  Google Scholar 

  7. Buller RE, Runnebaum IB, Karlan B, Horowitz JA, et al. A phase I/II trial of rAd-p53 (SCH 58500) gene replacement in recurrent ovarian cancer. Cancer Gene Ther. 2002;9:553–566.

    Article  CAS  Google Scholar 

  8. Nemunaitis J, Swisher SG, Timmons T, et al. Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. J Clin Oncol. 2000;18:609–622.

    Article  CAS  Google Scholar 

  9. Albelda SM, Wiewrodt R, Sterman DH . Gene therapy for lung neoplasms. Clin Chest Med. 2002;23:265–277.

    Article  Google Scholar 

  10. Alvarez RD, Barnes MN, Gomez-Navarro H, et al. A cancer gene therapy approach utilizing an anti-erbB-2 single-chain antibody-encoding adenovirus (AD21): a phase I trial. Clin Cancer Res. 2000;6:3081–3087.

    CAS  PubMed  Google Scholar 

  11. Crystal RG, Mcelvaney NG, Rosenfeld MA, et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet. 1994;8:42–51.

    Article  CAS  Google Scholar 

  12. Sterman DH, Treat J, Litzky LA, et al. Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther. 1998;9:1083–1092.

    Article  CAS  Google Scholar 

  13. Hasenburg A, Tong XW, Fischer DC, et al. Adenovirus-mediated thymidine kinase gene therapy in combination with Topotecan for patients with recurrent ovarian cancer: 2.5-year follow-up. Gynecol Oncol. 2001;83:549–554.

    Article  CAS  Google Scholar 

  14. Benihoud K, Saggio I, Opolon P, et al. Efficient repeated adenovirus-mediated gene transfer in mice lacking both tumor necrosis factor alpha and lymphotoxin α. J Virol. 1998;72:9514–9525.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Dong JY, Wang D, Van Ginkel FW, et al. Systematic analysis of repeated gene delivery into animal lungs with a recombinant adenovirus vector. Hum Gene Ther. 1996;7: 319–331.

    Article  CAS  Google Scholar 

  16. Ozbun MA, Butel JS . Tumor suppressor p53 mutations and breast cancer: a critical analysis. Adv Cancer Res. 1995;66:71–141.

    Article  CAS  Google Scholar 

  17. Selter H, Montenarh M . The emerging picture of p53. Int J Biochem. 1994;26:145–154.

    Article  CAS  Google Scholar 

  18. Miyashita T, Krajewski S, Krajewska M, et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994;9:1799–1805.

    CAS  PubMed  Google Scholar 

  19. Miyashita T, Reed JC . Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995;80:293–299.

    Article  CAS  Google Scholar 

  20. Somasundaram K, El-Deiry WS . Tumor suppressor p53: regulation and function. Frontiers Biosci 2000;5:d424–d437.

    Article  CAS  Google Scholar 

  21. El-Deiry WS, Harper JW, O'connor PM, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994;54:1169–1174.

    CAS  PubMed  Google Scholar 

  22. El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993;75:817–825.

    Article  CAS  Google Scholar 

  23. Kitanaka C, Namiki T, Noguchi K, et al. Caspase-dependent apoptosis of COS-7 cells induced by Bax overexpression: differential effects of Bcl2 and Bcl-xL on Bax-induced caspase activation and apoptosis. Oncogene. 1997;15:1763–1772.

    Article  CAS  Google Scholar 

  24. Chen Cy, Oliner Jd, Zhan Q, et al. Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc Natl Acad Sci. 1994;91:2684–2688.

    Article  CAS  Google Scholar 

  25. Oliner JD, Pietenpol JA, Thiagalingam S, et al. Oncoprotein MDM2 conceals the activation domain of tumor suppressor p53. Nature 1993;362:857–860.

    Article  CAS  Google Scholar 

  26. Wen SF, Xie L, Mcdonald M, et al. Development and validation of sensitive assays to quantitate gene expression after p53 gene therapy and paclitaxel chemotherapy using in vivo dosing in tumor xenograft models. Cancer Gene Ther. 2000;7:1469–1480.

    Article  CAS  Google Scholar 

  27. Wills KN, Maneval DC, Menzel P, et al. Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. Hum Gene Ther. 1994;5:1079–1088.

    Article  CAS  Google Scholar 

  28. Huyghe BG, Liu X, Sutjipto S, et al. Purification of a type 5 recombinant adenovirus encoding human p53 by column chromatography. Hum Gene Ther. 1995;6:1403–1416.

    Article  CAS  Google Scholar 

  29. Maizel JV Jr, White DO, Scharff MD . The polypeptides of adenovirus. I. Evidence for multiple protein components in the virion and a comparison of types 2, 7A, and 12. Virology 1968;36:115–125.

    Article  CAS  Google Scholar 

  30. Shahin MS, Hughes JH, Sood AK, et al. The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma. Cancer 2000;89:2006–2017.

    Article  CAS  Google Scholar 

  31. Grace M, Xie L, Musco ML, et al. The use of laser scanning cytometry to assess depth of penetration of adenovirus p53 gene therapy in human xenograft biopsies. Am J Pathol. 1999;155:1869–1877.

    Article  CAS  Google Scholar 

  32. Mirza A, McGuirk M, Hockenberry T, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 2002;21:2613–2622.

    Article  CAS  Google Scholar 

  33. Boylay JL, Perruchoud AP, Reuter J, et al. p21 gene expression as an indicator for the activity of adenovirus-p53 gene therapy in non-small cell lung cancer patients. Cancer Gene Ther. 2000;7:1215–1219.

    Article  Google Scholar 

  34. Bursch W, Kleine L, Tenniswood M . The biochemistry of cell death by apoptosis. Biochem Cell Biol. 1990;68:1071–1074.

    Article  CAS  Google Scholar 

  35. Stallwood Y, Fisher KD, Gallimore PH, Mautner V . Neutralisation of adenovirus infectivity by ascitic fluid from ovarian cancer patients. Gene Ther. 2000;7:637–643.

    Article  CAS  Google Scholar 

  36. Molan-Kimber KL, Sterman DH, Chang M, et al. Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma. Hum Gene Ther. 1998;14:2121–2133.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the patients and their families for their participation in this bioanalytical cohort of the trial. We thank Michelle Kerin and Melanie Hattermann for the tremendous effort they put in coordinating study samples. We would also like to thank Dr. Suxing Liu for her helpful discussion of the survivin data.

Author information

Authors and Affiliations

  1. Canji, Inc., San Diego, California, USA

    Shu Fen Wen, Erlinda Quijano, Jeremy Shinoda, Dan Maneval & Beth Hutchins

  2. The University of Iowa Hospital and Clinic, Iowa City, Iowa, USA

    Vikas Mahavni & Richard Buller

  3. Schering-Plough Research Institute, Kenilworth and Union, New Jersey, USA

    Michael Grace, Mary Lynn Musco-Hobkinson, Tong-Yuan Yang, Yuetian Chen & JoAnn Horowitz

  4. Universitäts-Frauenklinik, Freiburg, Germany

    Ingo Runnenbaum

Authors
  1. Shu Fen Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vikas Mahavni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erlinda Quijano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeremy Shinoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Grace
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mary Lynn Musco-Hobkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tong-Yuan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuetian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ingo Runnenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. JoAnn Horowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dan Maneval
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Beth Hutchins
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Richard Buller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shu Fen Wen.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wen, S., Mahavni, V., Quijano, E. et al. Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer. Cancer Gene Ther 10, 224–238 (2003). https://doi.org/10.1038/sj.cgt.7700562

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700562

Keywords

  • rAd-p53
  • ovarian cancer
  • gene therapy
  • QPCR
  • SCH 58500

This article is cited by

Search

Advanced search

Quick links