title: Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy.
abstract: OBJECTIVE
  The inhibitory role of secreted chondroitin sulfate proteoglycans on oncolytic viral (OV) therapy was examined. Chondroitinase ABC (Chase-ABC) is a bacterial enzyme that can remove chondroitin sulfate glycosaminoglycans from proteoglycans without any deleterious effects in vivo. We examined the effect of Chase-ABC on OV spread and efficacy.
  
  
  METHODS
  Three-dimensional glioma spheroids placed on cultured brain slices were utilized to evaluate OV spread. Replication-conditional OV-expressing Chase-ABC (OV-Chase) was engineered using HSQuik technology and tested for spread and efficacy in glioma spheroids. Subcutaneous and intracranial glioma xenografts were utilized to compare antitumor efficacy of OV-Chase, rHsvQ (control), and PBS. Titration of viral particles was performed from OV-treated subcutaneous tumors. Glioma invasion was assessed in collagen-embedded glioma spheroids in vitro and in intracranial tumors. All statistical tests were two sided.
  
  
  RESULTS
  Treatment with Chase-ABC in cultured glioma cells significantly enhanced OV spread in glioma spheroids grown on brain slices (P < 0.0001). Inoculation of subcutaneous glioma xenografts with Chase-expressing OV significantly increased viral titer (>10 times, P = 0.0008), inhibited tumor growth, and significantly increased overall animal survival (P < 0.006) compared with treatment with parental rHsvQ virus. Single OV-Chase administration in intracranial xenografts also resulted in longer median survival of animals than rHsvQ treatment (32 vs. 21 days, P < 0.018). Glioma cell migration and invasion were not increased by OV-Chase treatment.
  
  
  CONCLUSIONS
  We conclude that degradation of glioma extracellular matrix with OV-expressing bacterial Chase-ABC enhanced OV spread and antitumor efficacy.
authors.affiliation: Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, Center for Biostatistics, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Dmitrieva
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.forename: Mariano
authors.initials: M
authors.lastname: Viapiano
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Glorioso
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D019765:Chondroitin ABC Lyase / Q000378:metabolism*; D002809:Chondroitin Sulfates / Q000737:chemistry*; D017353:Gene Deletion; D005910:Glioma; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D050504:Oncolytic Viruses; D011509:Proteoglycans / Q000737:chemistry; D000097573:Red Fluorescent Protein
chemical_list: D000970:Antineoplastic Agents; D019765:Chondroitin ABC Lyase; D002809:Chondroitin Sulfates; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D011509:Proteoglycans; D000097573:Red Fluorescent Protein; C038142:chondroitin sulfate glycosaminoglycan