Differential effects of combined Ad5-Δ24RGD and radiation therapy in in vitro versus in vivo models of malignant glioma

Martine L.M. Lamfers, Sander Idema, Lisette Bosscher, Stan Heukelom, Sharif Moeniralm, Ida H. Van Der Meulen-Muileman, Renée M. Overmeer, Paul Van Der Valk, Victor W. Van Beusechem, Winald R. Gerritsen, W. Peter Vandertop, Clemens M.F. Dirven

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Abstract

Purpose: The integrin-targeted conditionally replicating adenovirus Ad5-Δ24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-Δ24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model. Experimental Design and Results: Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-Δ24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-Δ24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-Δ24RGD with 1 x 5 Gy total body irradiation or with 2 x 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-Δ24RGD. Conclusions: Combined treatment with Ad5-Δ24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.

Original languageEnglish (US)
Pages (from-to)7451-7458
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number24
DOIs
StatePublished - Dec 15 2007

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lamfers, M. L. M., Idema, S., Bosscher, L., Heukelom, S., Moeniralm, S., Van Der Meulen-Muileman, I. H., Overmeer, R. M., Van Der Valk, P., Van Beusechem, V. W., Gerritsen, W. R., Vandertop, W. P., & Dirven, C. M. F. (2007). Differential effects of combined Ad5-Δ24RGD and radiation therapy in in vitro versus in vivo models of malignant glioma. Clinical Cancer Research, 13(24), 7451-7458. https://doi.org/10.1158/1078-0432.CCR-07-1265