title: Copper chelation enhances antitumor efficacy and systemic delivery of oncolytic HSV.
abstract: OBJECTIVE
  Copper in serum supports angiogenesis and inhibits replication of wild-type HSV-1. Copper chelation is currently being investigated as an antiangiogenic and antineoplastic agent in patients diagnosed with cancer. Herpes simplex virus-derived oncolytic viruses (oHSV) are being evaluated for safety and efficacy in patients, but several host barriers limit their efficacy. Here, we tested whether copper inhibits oHSV infection and replication and whether copper chelation would augment therapeutic efficacy of oHSV.
  
  
  METHODS
  Subcutaneous and intracranial tumor-bearing mice were treated with oHSV ± ATN-224 to evaluate tumor burden and survival. Virus replication and cell killing was measured in the presence or absence of the copper chelating agent ATN-224 and in the presence or absence of copper in vitro. Microvessel density and changes in perfusion were evaluated by immunohistochemistry and dynamic contrast enhanced MRI (DCE-MRI). Serum stability of oHSV was measured in mice fed with ATN-224. Tumor-bearing mice were injected intravenously with oHSV; tumor burden and amount of virus in tumor tissue were evaluated.
  
  
  RESULTS
  Combination of systemic ATN-224 and oHSV significantly reduced tumor growth and prolonged animal survival. Immunohistochemistry and DCE-MRI imaging confirmed that ATN-224 reduced oHSV-induced blood vessel density and vascular leakage. Copper at physiologically relevant concentrations inhibited oHSV replication and glioma cell killing, and this effect was rescued by ATN-224. ATN-224 increased serum stability of oHSV and enhanced the efficacy of systemic delivery.
  
  
  CONCLUSIONS
  This study shows that combining ATN-224 with oHSV significantly increased serum stability of oHSV and greatly enhanced its replication and antitumor efficacy.
authors: Dardinger Laboratory for Neuro-oncology and Neurosciences, Northwestern University, Evanston, Illinois, USA.
authors: Ji Young
authors: JY
authors: Yoo
authors: Jason
authors: J
authors: Pradarelli
authors: Amy
authors: A
authors: Haseley
authors: Jeffrey
authors: J
authors: Wojton
authors: Azeem
authors: A
authors: Kaka
authors: Anna
authors: A
authors: Bratasz
authors: Christopher A
authors: CA
authors: Alvarez-Breckenridge
authors: Jun-Ge
authors: JG
authors: Yu
authors: Kimerly
authors: K
authors: Powell
authors: Andrew P
authors: AP
authors: Mazar
authors: Theodoros N
authors: TN
authors: Teknos
authors: E Antonio
authors: EA
authors: Chiocca
authors: Joseph C
authors: JC
authors: Glorioso
authors: Matthew
authors: M
authors: Old
authors: Balveen
authors: B
authors: Kaur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003300:Copper; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005910:Glioma / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008982:Molybdenum / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D018139:Simplexvirus / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate