title: Therapeutic concentrations of anti-epileptic drugs do not inhibit the activity of the oncolytic adenovirus Delta24-RGD in malignant glioma.
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.
authors.affiliation: Department of Neurosurgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jonas
authors.initials: J
authors.lastname: de Jonge
authors.forename: Lotte M E
authors.initials: LM
authors.lastname: Berghauser Pont
authors.forename: Sander
authors.initials: S
authors.lastname: Idema
authors.forename: Jenneke J
authors.initials: JJ
authors.lastname: Kloezeman
authors.forename: David
authors.initials: D
authors.lastname: Noske
authors.forename: Clemens M F
authors.initials: CM
authors.lastname: Dirven
authors.forename: Martine L M
authors.initials: ML
authors.lastname: Lamfers
mesh_terms: D000256:Adenoviridae / Q000187:drug effects*; D000927:Anticonvulsants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D000077287:Levetiracetam; D008156:Luciferases; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000187:drug effects*; D010672:Phenytoin; D010889:Piracetam / Q000031:analogs & derivatives; D014635:Valproic Acid
chemical_list: D000927:Anticonvulsants; D000077287:Levetiracetam; D014635:Valproic Acid; D010672:Phenytoin; D008156:Luciferases; D010889:Piracetam