Cyclophosphamide Increases Transgene Expression Mediated by an Oncolytic Adenovirus in Glioma-Bearing Mice Monitored by Bioluminescence Imaging

Martine L.M. Lamfers, Giulia Fulci, Davide Gianni, Yi Tang, Kazuhiko Kurozumi, Balveen Kaur, Sharif Moeniralm, Yoshinaga Saeki, Jan E. Carette, Ralph Weissleder, W. Peter Vandertop, Victor W. van Beusechem, Clemens M.F. Dirven, E. Antonio Chiocca

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71 Citations (Scopus)

Abstract

Approaches to improve the oncolytic potency of replication-competent adenoviruses include the insertion of therapeutic transgenes into the viral genome. Little is known about the levels and duration of in vivo transgene expression by cells infected with such "armed" viruses. Using a tumor-selective adenovirus encoding firefly luciferase (AdΔ24CMV-Luc) we investigated these questions in an intracranial mouse model for malignant glioma. Luciferase expression was detected by bioluminescence imaging, and the effect of the immunosuppressive agent cyclophosphamide (CPA) on transgene expression was assessed. Intratumoral AdΔ24CMV-Luc injection led to a localized dose-dependent expression of luciferase. Surprisingly, this expression decreased rapidly during the course of 14 days. In contrast, mice injected with nonreplicating Ad.CMV-Luc demonstrated stable transgene expression. Treatment of mice with CPA in combination with AdΔ24CMV-Luc retarded the loss of transgene expression. Staining of mouse brains for inflammatory cells demonstrated decreased tumor infiltration by immune cells in CPA-treated mice. Moreover, in immunodeficient NOD/SCID mice loss of transgene expression was less rapid and not prevented by CPA treatment. Together, our data demonstrate that transgene expression and viral replication decrease rapidly after intratumoral injection of oncolytic adenovirus in mouse brains and that treatment with the immunomodulator CPA prolongs viral-mediated gene expression.

Original languageEnglish
Pages (from-to)779-788
Number of pages10
JournalMolecular Therapy
Volume14
Issue number6
DOIs
Publication statusPublished - Dec 1 2006
Externally publishedYes

Keywords

  • bioluminescence imaging
  • glioma
  • immune suppression
  • oncolytic adenovirus
  • transgene expression

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Lamfers, M. L. M., Fulci, G., Gianni, D., Tang, Y., Kurozumi, K., Kaur, B., Moeniralm, S., Saeki, Y., Carette, J. E., Weissleder, R., Vandertop, W. P., van Beusechem, V. W., Dirven, C. M. F., & Chiocca, E. A. (2006). Cyclophosphamide Increases Transgene Expression Mediated by an Oncolytic Adenovirus in Glioma-Bearing Mice Monitored by Bioluminescence Imaging. Molecular Therapy, 14(6), 779-788. https://doi.org/10.1016/j.ymthe.2006.08.008