Development of an optimized conditionally replicative adenoviral agent for ovarian cancer

Zeng B. Zhu, Baogen Lu, Miey Park, Sharmila K. Makhija, Thomas M. Numnum, James E. Kendrick, Minghui Wang, Yuko Tsuruta, Paul Fisher, Ronald D. Alvarez, Fen Zhou, Gene P. Siegal, Hongju Wu, David T. Curiel

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Human ovarian cancer is a highly lethal malignant neoplasm in woman with no effective treatment if conventional chemotherapy fails. In this regard, conditionally replicative adenoviruses (CRAds) represent a promising new modality for the treatment of cancer. A key contribution to the development of CRAds was the introduction of tumor-selective viral replication to restrict amplification to the neoplastic cell population. Under ideal conditions following cellular infection, the viruses replicate selectively in the infected tumor cells, killing the cells by cytolysis, leaving normal cells unaffected. However, to date, there have been limitations to the clinical application of these CRAd agents i.e. poor viral infectivity, poor tumor specificity and high toxicity. Here, we report the in vitro and in vivo comparison of four CRAd agents developed for ovarian cancer application, specifically, Ad-Δ24.F5/3, CRAd-C.F5/3, CRAd-M.F5/3 and CRAd-S.F5/3. All CRAd agents contained fiber knob chimeras of adenovirus serotype 3, which enhanced the viral infectivity at the transductional level via a non-Coxsackie-Adenovirus Receptor alternative pathway. In addition, these CRAds embodied distinct mechanisms for the achievement of replication specificity. Tumor cell killing was assessed by using an oncolytic assay and a cell viability assay (MTS) in vitro, while tumor growth was examined in a xenograft model in vivo by using a bioluminescent imaging assay. In addition, the replication rates of the CRAd agents were determined in human liver slices. Both the Ad-Δ24.F5/3 and CRAd-S.F5/3 were demonstrated to have higher tumor killing effects in tumor cells and a lower viral replication rate in human liver. These agents are thus excellent candidates for clinical trials of CRAd agents against human ovarian cancer.

Original languageEnglish (US)
Pages (from-to)1179-1188
Number of pages10
JournalInternational journal of oncology
Volume32
Issue number6
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

Keywords

  • Adenovirus
  • Conditionally replicative adenovirus
  • Fiber modification
  • Tumor specific promoter

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Zhu, Z. B., Lu, B., Park, M., Makhija, S. K., Numnum, T. M., Kendrick, J. E., Wang, M., Tsuruta, Y., Fisher, P., Alvarez, R. D., Zhou, F., Siegal, G. P., Wu, H., & Curiel, D. T. (2008). Development of an optimized conditionally replicative adenoviral agent for ovarian cancer. International journal of oncology, 32(6), 1179-1188. https://doi.org/10.3892/ijo_32_6_1179