Targeting mesothelioma using an infectivity enhanced survivin-conditionally replicative adenoviruses

Zeng B. Zhu, Sharmila K. Makhija, Baogen Lu, Minghui Wang, Shuyi Wang, Koichi Takayama, Gene P. Siegal, Paul N. Reynolds, David T. Curiel

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Mesothelioma is a highly malignant neoplasm with no effective treatment. Conditionally replicative adenoviruses (CRAds) represent a promising new modality for the treatment of cancer in general. A key contribution in this regard is the introduction of tumor-selective viral replication for amplification of the initial inoculum in the neoplastic cell population. Under ideal conditions following cellular infection, the viruses replicate selectively in the infected tumor cells and kill the cells by cytolysis, leaving normal cells unaffected. However, to date there have been two limitations to clinical application of these CRAd agents; viral infectivity and tumor specificity have been poor. Herein we report on two CRAd agents, CRAd-S.RGD and CRAd-S.F5/3, in which the tumor specificity is regulated by a tumor-specific promoter, the survivin promoter, and the viral infectivity is enhanced by incorporating a capsid modification (RGD or F5/3) in the adenovirus fiber region. These CRAd agents effectively target human mesothelioma cell lines, induce strong cytoxicity in these cells in vitro, and viral replication in a H226 murine xenograft model in vivo. In addition, the survivin promoter has extremely low activity both in the non-transformed cell line, HMEC, and in human liver tissue. Our results suggest that the survivin-based CRAds are promising agents for targeting mesothelioma with low host toxicity. These agents should provide important insights into the identification of novel therapeutic strategies for mesothelioma.

Original languageEnglish (US)
Pages (from-to)701-711
Number of pages11
JournalJournal of Thoracic Oncology
Volume1
Issue number7
StatePublished - Sep 1 2006
Externally publishedYes

Keywords

  • Adenoviral vector and mesothelioma
  • Survivin gene
  • Transcriptional targeting
  • Tumor-specific promoter

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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  • Cite this

    Zhu, Z. B., Makhija, S. K., Lu, B., Wang, M., Wang, S., Takayama, K., Siegal, G. P., Reynolds, P. N., & Curiel, D. T. (2006). Targeting mesothelioma using an infectivity enhanced survivin-conditionally replicative adenoviruses. Journal of Thoracic Oncology, 1(7), 701-711.