title: Oncolytic herpes simplex virus mutants are more efficacious than wild-type adenovirus Type 5 for the treatment of high-risk neuroblastomas in preclinical models.
abstract: BACKGROUND
  High-risk neuroblastoma (Nb) is incurable using current treatment regimens in the majority of patients. Oncolytic virotherapy is a novel approach being tested for several types of adult cancers.
  
  
  OBJECTIVE
  To compare the susceptibility of Nb tumor models to oncolytic adenovirus and HSV mutants and delineate the mechanisms of resistance or sensitivity.
  
  
  METHODS
  Human Nb cell lines were used to determine susceptibility to adenovirus type 5 wild-type and HSV1 mutant (NV1066) infection, adenovirus receptor expression, support of NV1066 replication, and induction of apoptosis. Human xenograft tumors in immunodeficient mice were evaluated for histological effects and tumor response to intratumoral injection of an oncolytic HSV mutant.
  
  
  RESULTS
  All eight Nb cell lines tested in culture were relatively resistant to infection with wild type and attenuated adenoviruses. Cells expressed the cocksackie-adenovirus attachment receptor (CAR) but had low or absent expression of the internalization receptors (alphavbeta3, alphavbeta5 integrins). In contrast, all cells were uniformly sensitive to infection with the attenuated HSV mutant, NV1066. Productive virus replication and induction of apoptosis were observed in HSV-infected cells. CHLA-20 and LAN-5 xenograft tumors injected with a single dose of NV1066 showed a significant antitumor response, and the animals had a prolonged survival post infection in comparison to the PBS-treated control group. HSV injected tumors showed extensive areas of necrosis and morphologic evidence of apoptosis.
  
  
  CONCLUSIONS
  Nb tumor models are resistant to adenovirus mediated oncolysis but highly sensitive to HSV mediated oncolysis. Further studies of HSV virotherapy as a novel treatment for Nb are warranted.
authors.affiliation: Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Nehal S
authors.initials: NS
authors.lastname: Parikh
authors.forename: Mark A
authors.initials: MA
authors.lastname: Currier
authors.forename: Yonatan Y
authors.initials: YY
authors.lastname: Mahller
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Adams
authors.forename: Betsy
authors.initials: B
authors.lastname: Di Pasquale
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
mesh_terms: D000260:Adenoviruses, Human / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004198:Disease Susceptibility; D006801:Humans; D016023:Integrins; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009336:Necrosis; D009374:Neoplasms, Experimental / Q000628:therapy; D009447:Neuroblastoma / Q000473:pathology / Q000628:therapy*; D011991:Receptors, Virus / Q000032:analysis / Q000502:physiology; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D014779:Virus Replication
chemical_list: C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016023:Integrins; D011991:Receptors, Virus