Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma

Zeng Bian Zhu, Yabing Chen, Sharmila K. Makhija, Baogen Lu, Minghui Wang, Angel A. Rivera, Masato Yamamoto, Shuyi Wang, Gene P. Siegal, David T. Curiel, Jay M. McDonald

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Cholangiocarcinoma 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 was 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 the clinical application of these CRAd agents, i.e. poor viral infectivity and tumor specificity. Here we report the construction of three new CRAd agents, CRAd-S.RGD, CRAd-S.F5/3 and CRAd-S.pk7, 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, F5/3 or pk7) in the adenovirus fiber region. These CRAd agents effectively target cholangiocarcinoma cells, induce strong cytoxicity in these cells in vitro and inhibit tumor growth in a 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 cholangiocarcinoma with low host toxicity. Such results should provide important insights into the identification of novel therapeutic strategies for cholangiocarcinoma.

Original languageEnglish (US)
Pages (from-to)1319-1329
Number of pages11
JournalInternational Journal of Oncology
Volume29
Issue number5
StatePublished - Nov 2006
Externally publishedYes

Fingerprint

Cholangiocarcinoma
Adenoviridae
Neoplasms
Capsid
Virus Diseases
Heterografts
Carcinogens
Cell Line
Liver

Keywords

  • Adenoviral vector
  • Cholangiocarcinoma
  • Conditionally replicative adenovirus
  • Survivin gene
  • Tumor-specific promoter

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zhu, Z. B., Chen, Y., Makhija, S. K., Lu, B., Wang, M., Rivera, A. A., ... McDonald, J. M. (2006). Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma. International Journal of Oncology, 29(5), 1319-1329.

Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma. / Zhu, Zeng Bian; Chen, Yabing; Makhija, Sharmila K.; Lu, Baogen; Wang, Minghui; Rivera, Angel A.; Yamamoto, Masato; Wang, Shuyi; Siegal, Gene P.; Curiel, David T.; McDonald, Jay M.

In: International Journal of Oncology, Vol. 29, No. 5, 11.2006, p. 1319-1329.

Research output: Contribution to journalArticle

Zhu, ZB, Chen, Y, Makhija, SK, Lu, B, Wang, M, Rivera, AA, Yamamoto, M, Wang, S, Siegal, GP, Curiel, DT & McDonald, JM 2006, 'Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma', International Journal of Oncology, vol. 29, no. 5, pp. 1319-1329.
Zhu, Zeng Bian ; Chen, Yabing ; Makhija, Sharmila K. ; Lu, Baogen ; Wang, Minghui ; Rivera, Angel A. ; Yamamoto, Masato ; Wang, Shuyi ; Siegal, Gene P. ; Curiel, David T. ; McDonald, Jay M. / Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma. In: International Journal of Oncology. 2006 ; Vol. 29, No. 5. pp. 1319-1329.
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