Targeting lung cancer using an infectivity enhanced CXCR4-CRAd

Zeng B. Zhu, Angel A. Rivera, Sharmila K. Makhija, Baogen Lu, Minghui Wang, Miiru Izumi, Robert J. Cerfolio, Mariam A. Stoff-Khalili, Fen Zhou, Koichi Takayama, Gene P. Siegal, David T. Curiel

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Conventional treatments are not adequate for the majority of lung cancer patients. Conditionally replicating adenoviruses (CRAds) represent a promising new modality for the treatment of neoplastic diseases, including non-small cell lung cancer. Specifically, following cellular infection, the virus replicates selectively in the infected tumor cells and kills the cells by cytolysis. Next, the progeny virions infect a new population of surrounding target cells, replicate again and eradicate the infected tumor cells while leaving normal cells unaffected. However, to date, there have been two main limitations to successful clinical application of these CRAd agents; i.e. poor infectivity and poor tumor specificity. Here we report the construction of a CRAd agent, CRAd-CXCR4.RGD, in which the adenovirus E1 gene is driven by a tumor-specific CXCR4 promoter and the viral infectivity is enhanced by a capsid modification, RGD4C. This agent CRAd-CXCR4.RGD, as expected, improved both of the viral infectivity and tumor specificity as evaluated in an established lung tumor cell line and in primary tumor tissue from multiple patients. As an added benefit, the activity of the CXCR4 promoter was low in human liver as compared to three other promoters regularly used for targeting tumors. In addition, this agent has the potential of targeting multiple other tumor cell types. From these data, the CRAd-CXCR4.RGD appears to be a promising novel CRAd agent for lung cancer targeting with low host toxicity.

Original languageEnglish (US)
Pages (from-to)145-156
Number of pages12
JournalLung Cancer
Volume55
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • Adenoviral vector
  • CXCR4 gene
  • Transcriptional targeting
  • Tumor-specific promoter

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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  • Cite this

    Zhu, Z. B., Rivera, A. A., Makhija, S. K., Lu, B., Wang, M., Izumi, M., Cerfolio, R. J., Stoff-Khalili, M. A., Zhou, F., Takayama, K., Siegal, G. P., & Curiel, D. T. (2007). Targeting lung cancer using an infectivity enhanced CXCR4-CRAd. Lung Cancer, 55(2), 145-156. https://doi.org/10.1016/j.lungcan.2006.10.012