Differential effects of combined Ad5-Delta 24RGD and radiation therapy in In vitro versus In vivo models of malignant glioma
Autor: | Victor W. van Beusechem, Renée M Overmeer, Paul van der Valk, Winald R. Gerritsen, Sander Idema, W. Peter Vandertop, Clemens M F Dirven, Ida H van der Meulen-Muileman, Martine L.M. Lamfers, Sharif Moeniralm, Lisette Bosscher, S. Heukelom |
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Přispěvatelé: | Neurosurgery, Hematology, Radiation Oncology, Pathology, Medical oncology, Amsterdam Neuroscience |
Rok vydání: | 2007 |
Předmět: |
Cancer Research
Pathology medicine.medical_specialty Combination therapy medicine.medical_treatment In Vitro Techniques Adenoviridae Mice In vivo Glioma Cell Line Tumor Spheroids Cellular medicine Animals Humans Oncolytic Virotherapy Radiotherapy business.industry Brain Neoplasms Cancer Total body irradiation medicine.disease Flow Cytometry Combined Modality Therapy Immunohistochemistry Xenograft Model Antitumor Assays Oncolytic virus Radiation therapy Oncology Cancer research Ovarian cancer business |
Zdroj: | Clinical Cancer Research, 13(24), 7451-7458. American Association for Cancer Research Inc. Clinical Cancer Research, 13(24), 7451-8. American Association for Cancer Research Inc. Clinical cancer research, 13(24), 7451-7458. American Association for Cancer Research Inc. 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-delta 24RGD and radiation therapy in in vitro versus in vivo models of malignant glioma ', Clinical Cancer Research, vol. 13, no. 24, pp. 7451-8 . https://doi.org/10.1158/1078-0432.CCR-07-1265 |
ISSN: | 1557-3265 1078-0432 |
Popis: | 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 × 5 Gy total body irradiation or with 2 × 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. |
Databáze: | OpenAIRE |
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