Chondroitinase ABC I―Mediated Enhancement of Oncolytic Virus Spread and Antitumor Efficacy

• Published in: Clinical cancer research 2011-03, Vol.17 (6), p.1362-1372
• Main Authors: DMITRIEVA, Nina, LIANBO YU, VIAPIANO, Mariano, CRIPE, Timothy P, CHIOCCA, E. Antonio, GLORIOSO, Joseph C, KAUR, Balveen
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Brain - metabolism; Brain Neoplasms - metabolism; Cell Line, Tumor; Chondroitin ABC Lyase - metabolism; Chondroitin Sulfates - chemistry; Gene Deletion; Glioma; Green Fluorescent Proteins - metabolism; Humans; Luminescent Proteins - metabolism; Medical sciences; Mice; Neoplasm Transplantation; Oncolytic Viruses; Pharmacology. Drug treatments; Proteoglycans - chemistry; Red Fluorescent Protein
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-2213

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. 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. 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. We conclude that degradation of glioma extracellular matrix with OV-expressing bacterial Chase-ABC enhanced OV spread and antitumor efficacy.