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Therapeutic concentrations of anti‐epileptic drugs do not inhibit the activity of the oncolytic adenovirus Delta24‐RGD in malignant glioma
Author(s) -
Jonge Jonas,
Berghauser Pont Lotte M. E.,
Idema Sander,
Kloezeman Jenneke J.,
Noske David,
Dirven Clemens M. F.,
Lamfers Martine L. M.
Publication year - 2013
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.2703
Subject(s) - oncolytic virus , oncolytic adenovirus , glioma , cell culture , cancer research , pharmacology , medicine , virology , virus , biology , genetics
Abstract Background The oncolytic adenovirus Delta24‐RGD is currently being tested in phase I trials for the treatment of glioblastoma (GBM). Literature suggests that frequently prescribed anticonvulsants for these patients, phenytoin (PHE), valproic acid (VPA) and levetiracetam (LEV), may interfere with cellular mechanisms of cancer or oncolytic virus activity. We therefore investigated the direct effects of these drugs on Delta24‐RGD infection and oncolytic activity. Methods The anticonvulsants PHE, VPA, and LEV were combined with Delta24‐RGD treatment in established glioma cell lines as well as on a panel of patient‐derived GBM cultures. Effects on infection efficiency were assessed using luciferase‐encoding adenoviral vectors. Oncolytic activity was determined by WST‐1 assay and viral progeny production was quantified by dilution titration. Results IC50 values of the anti‐epileptic drugs on the four glioma cell lines were far above clinically‐relevant concentrations. At therapeutic concentrations, the anti‐epileptics generally did not alter the infection efficiency of RGD‐modified adenovirus, nor affect progeny production or oncolytic activity of Delta24‐RGD. The only exception was found in U373 cells, where VPA slightly antagonised the oncolytic effect of Delta24‐RGD (from 29% to 55% viability, p<0.01) as well as viral progeny production (60% decrease, p<0.01). Oncolysis by Delta24‐RGD was not inhibited by the anti‐epileptics in any of the patient‐derived glioma cultures (n=6). In fact, in one culture a slight enhancement of viral oncolysis by PHE and LEV was found, from 89.7% viability to 76% and 62.4%, respectively (p<0.01) Conclusions Therapeutic levels of valproic acid, phenytoin and levetiracetam do not negatively interfere with the infection efficiency or oncolytic activity of Delta24‐RGD in patient‐derived GBM cells. Therefore, there is no indication that the choice of anticonvulsant for seizure control in glioma patients should take treatment with Delta24‐RGD into account. Copyright © 2013 John Wiley & Sons, Ltd.