Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy.
Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy.
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DOI：
10.1158/1078-0432.ccr-10-2213
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发表时间：
2011-03-15
期刊：
影响因子：
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通讯作者：
Kaur B
中科院分区：
文献类型：
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作者：
Dmitrieva N;Yu L;Viapiano M;Cripe TP;Chiocca EA;Glorioso JC;Kaur B
检查分泌的硫酸软骨素蛋白聚糖（CSPG）对溶瘤病毒（OV）治疗的抑制作用。软骨素酶ABC（Chase-ABC）是一种细菌酶，其可以从蛋白聚糖中去除硫酸软骨素糖基-氨基聚糖而在体内没有任何有害作用。我们检查了Chase-ABC对OV传播和功效的影响。三维胶质瘤球体放置在培养的脑切片上用于评估OV扩散。使用HSQuik技术工程化表达Chase-ABC的复制条件OV（OV-Chase），并测试其在胶质瘤球状体中的扩散和功效。利用皮下和颅内胶质瘤异种移植物来比较OV-Chase、rHsvQ（对照）和PBS的抗肿瘤功效。从OV处理的皮下肿瘤进行病毒颗粒的滴定。胶质瘤侵袭在体外胶原包埋胶质瘤球体和颅内肿瘤中进行评估。所有统计检验均为双侧检验。在培养的胶质瘤细胞中用Chase-ABC处理显著增强了OV在脑切片上生长的胶质瘤球体中的扩散（P< 0.0001）。与用亲本rHsvQ病毒治疗相比，用表达Chase的OV接种皮下胶质瘤异种移植物显著增加病毒滴度（> 10倍，P=0.0008），抑制肿瘤生长并显著增加总动物存活率（P<0.006）。与rHsvQ相比，在颅内异种移植物中单次给予OV-Chase也导致动物的中位生存期更长（32天对21天，P<0.018）。胶质瘤细胞迁移和侵袭没有增加OV-Chase治疗。我们得出结论，通过OV表达细菌Chase-ABC降解胶质瘤ECM增强OV扩散和抗肿瘤功效。
The inhibitory role of secreted Chondroitin-sulfate-proteoglycans (CSPGs) on Oncolytic viral (OV) therapy was examined. Chondroitinase ABC (Chase-ABC) is a bacterial enzyme that can remove chondroitin sulfate glycoso-amino glycans 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 xenograft, were utilized to compare anti-tumor 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 by 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 to treatment with parental rHsvQ virus. Single OV-Chase administration in intracranial xenografts also resulted in longer median survival of animals compared to rHsvQ (32 versus 21 days, P<0.018). Glioma cell migration and invasion were not increased by OV-Chase treatment. We conclude that degradation of glioma ECM by OV expressing bacterial Chase-ABC enhanced OV spread and anti-tumor efficacy.