Differential effects of combined Ad5- delta 24RGD and radiation therapy in in vitro versus in vivo models of malignant glioma.
OBJECTIVE
The integrin-targeted conditionally replicating adenovirus Ad5-delta 24RGD 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-delta 24RGD 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.


RESULTS
Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-delta 24RGD 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-delta 24RGD 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-delta 24RGD 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-delta 24RGD.


CONCLUSIONS
Combined treatment with Ad5-delta 24RGD 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.
Lamfers
Martine L M
ML
Department of Neurosurgery, VU University Medical Center, Amsterdam, the Netherlands. M.Lamfers@erasmusmc.nl
Idema
Sander
S
Bosscher
Lisette
L
Heukelom
Stan
S
Moeniralm
Sharif
S
van der Meulen-Muileman
Ida H
IH
Overmeer
Renée M
RM
van der Valk
Paul
P
van Beusechem
Victor W
VW
Gerritsen
Winald R
WR
Vandertop
W Peter
WP
Dirven
Clemens M F
CM
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D005910:Glioma / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D011878:Radiotherapy; D018874:Spheroids, Cellular; D023041:Xenograft Model Antitumor Assays