Inter-patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy

John T. Lam, Anna Kanerva, Gerd J. Bauerschmitz, Koichi Takayama, Kaori Suzuki, Masato Yamamoto, Snehal M. Bhoola, Bin Liu, Minghui Wang, Mack N. Barnes, Ronald D. Alvarez, Gene P. Siegal, David T. Curiel, Akseli Hemminki

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Background: Gene therapy offers a new strategy for cancer treatment. Adenoviruses represent the most widely used gene therapy vector and feature an excellent safety record. Conditionally replicative adenoviruses (CRAds) effect solid tumor penetration and tumor selective oncolysis and consequently offer potential efficacy for metastatic disease treatment. We evaluated five CRAds as candidate clinical agents for ovarian cancer therapy: RGDCRADcox-2R, Ad5VEGFE1, Ad5/3VEGFE1, Ad5-Δ24RGD, and Ad5/3-Δ24. Methods: DNA replication by these five CRAds, wild-type adenovirus, and an E1-deleted control was measured in purified primary ovarian cancer cell spheroids by quantitative PCR. CRAd-mediated oncolysis was quantified in ovarian cancer cell monolayers and three-dimensional spheroids by cellular viability assays. The therapeutic efficacy of each CRAd was tested by intraperitoneal administration in mice with peritoneally disseminated human ovarian cancer. Results: An increase in viral DNA was noted in primary tumor cell spheroids for all replicative viruses tested. Variation was noted in viral DNA replication between patient samples. All five CRAds induced remarkable oncolysis. They also prolonged survival in vivo compared with the wild-type control group. Conclusions: All five CRAds tested showed robust DNA replication, oncolysis, and in vivo therapeutic efficacy. Each virus has potential for clinical testing, and such further testing will ultimately determine its safety and relative usefulness. Variation of CRAd DNA replication between different patient samples suggests that target tissue features, such as surface receptors and endogenous transcription factors, may affect CRAd infectivity and replicativity. Evaluation of such factors may become important to optimize cancer therapy for individual patients.

Original languageEnglish
Pages (from-to)1333-1342
Number of pages10
JournalJournal of Gene Medicine
Volume6
Issue number12
DOIs
StatePublished - Dec 2004

Keywords

  • Adenovirus
  • Gene therapy
  • Oncolytic virus
  • Ovarian cancer
  • Replication-competent viruses
  • Translational research

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    Lam, J. T., Kanerva, A., Bauerschmitz, G. J., Takayama, K., Suzuki, K., Yamamoto, M., Bhoola, S. M., Liu, B., Wang, M., Barnes, M. N., Alvarez, R. D., Siegal, G. P., Curiel, D. T., & Hemminki, A. (2004). Inter-patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy. Journal of Gene Medicine, 6(12), 1333-1342. https://doi.org/10.1002/jgm.635