title: Enhanced antitumor efficacy of low-dose Etoposide with oncolytic herpes simplex virus in human glioblastoma stem cell xenografts.
abstract: OBJECTIVE
  Glioblastoma (GBM) inevitably recurs despite surgery, radiation, and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSC), has been implicated in this recurrence. The chemotherapeutic agent etoposide is generally reserved for treating recurrent tumors; however, its effectiveness is limited due to acute and cumulative toxicities to normal tissues. We investigate a novel combinatorial approach of low-dose etoposide with an oncolytic HSV to enhance antitumor activity and limit drug toxicity.
  
  
  METHODS
  In vitro, human GBM cell lines and GSCs were treated with etoposide alone, oncolytic herpes simplex virus (oHSV) G47Δ alone, or the combination. Cytotoxic interactions were analyzed using the Chou-Talalay method, and changes in caspase-dependent apoptosis and cell cycle were determined. In vivo, the most etoposide-resistant human GSC, BT74, was implanted intracranially and treated with either treatment alone or the combination. Analysis included effects on survival, therapy-associated adverse events, and histologic detection of apoptosis.
  
  
  RESULTS
  GSCs varied in their sensitivity to etoposide by over 50-fold in vitro, whereas their sensitivity to G47Δ was similar. Combining G47Δ with low-dose etoposide was moderately synergistic in GSCs and GBM cell lines. This combination did not enhance virus replication, but significantly increased apoptosis. In vivo, the combination of a single cycle of low-dose etoposide with G47Δ significantly extended survival of mice-bearing etoposide-insensitive intracranial human GSC-derived tumors.
  
  
  CONCLUSIONS
  The combination of low-dose etoposide with G47Δ increases survival of mice-bearing intracranial human GSC-derived tumors without adverse side effects. These results establish this as a promising combination strategy to treat resistant and recurrent GBM.
authors: Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, USA.
authors: Tooba A
authors: TA
authors: Cheema
authors: Ryuichi
authors: R
authors: Kanai
authors: Geon Woo
authors: GW
authors: Kim
authors: Hiroaki
authors: H
authors: Wakimoto
authors: Brent
authors: B
authors: Passer
authors: Samuel D
authors: SD
authors: Rabkin
authors: Robert L
authors: RL
authors: Martuza
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000628:therapy*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005047:Etoposide / Q000008:administration & dosage* / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy / Q000628:therapy*; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D058953:Neural Stem Cells / Q000473:pathology; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism; D018139:Simplexvirus / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D005047:Etoposide; D000077146:Irinotecan; D002166:Camptothecin