An adenovirus with enhanced infectivity mediates molecular chemotherapy of ovarian cancer cells and allows imaging of gene expression

Akseli Hemminki, Natalya Belousova, Kurt R. Zinn, Bin Liu, Minghui Wang, Tandra R. Chaudhuri, Buck E. Rogers, Donald J. Buchsbaum, Gene P. Siegal, Mack N. Barnes, Jesus Gomez-Navarro, David T. Curiel, Ronald D. Alvarez

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

The adenovirus (Ad) is a useful vector for cancer gene therapy due to its unparalleled gene transfer efficiency to dividing and quiescent cells. Primary cancer cells, however, often have highly variable or low levels of the requisite coxsackie-adenovirus receptor (CAR). Also, assessment of gene transfer and vector persistence has been logistically difficult in human clinical trials. We describe here two novel bicistronic adenoviral (Ad) vectors, AdTKSSTR and RGDTKSSTR, which contain the herpes simplex virus thymidine kinase gene (TK) for molecular chemotherapy and bystander effect. In addition, the viruses contain the human somatostatin receptor subtype-2 gene (SSTR2), the expression of which can be noninvasively imaged. We enhanced the infectivity of RGDTKSSTR by genetically incorporating the RGD-4C motif into the HI-loop of the fiber. This allows the virus to circumvent CAR deficiency by binding to αvβ3 and αvβ5 integrins, which are highly expressed on most ovarian cancers. The expanded tropism of RGDTKSSTR results in increased infectivity of purified primary ovarian cancer cells and allows enhanced gene transfer in the presence of malignant ascites containing anti-Ad antibodies. RGDTKSSTR may be a useful agent for treating ovarian cancer in clinical trials.

Original languageEnglish
Pages (from-to)223-231
Number of pages9
JournalMolecular Therapy
Volume4
Issue number3
DOIs
StatePublished - Jan 1 2001
Externally publishedYes

Keywords

  • Adenovirus
  • Cancer
  • Gene therapy
  • Imaging
  • Ovarian cancer
  • Somatostatin receptor
  • Targeting
  • Thymidine kinase

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    Hemminki, A., Belousova, N., Zinn, K. R., Liu, B., Wang, M., Chaudhuri, T. R., Rogers, B. E., Buchsbaum, D. J., Siegal, G. P., Barnes, M. N., Gomez-Navarro, J., Curiel, D. T., & Alvarez, R. D. (2001). An adenovirus with enhanced infectivity mediates molecular chemotherapy of ovarian cancer cells and allows imaging of gene expression. Molecular Therapy, 4(3), 223-231. https://doi.org/10.1006/mthe.2001.0446