Division of Tumor Virology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Clin Cancer Res. 2011 Aug 15;17(16):5333-42. doi: 10.1158/1078-0432.CCR-10-3124. Epub 2011 Jun 29.
In previous studies, we have shown that the apathogenic rat parvovirus H-1 (H-1PV) is capable to induce regression of advanced symptomatic rat and human gliomas in a rat model, when the virus was injected in the tumor (intracranially) or intravenously. Infection with H-1PV did not provoke any pathology in nontumor tissue. This study addresses the question whether also intranasal application of this oncolytic virus is suitable and sufficient for treating gliomas in this animal model.
Rat (RG-2) or human (U87) glioma cells were grafted stereotactically in the brain of rats (Wistar or RNU, respectively), and after development of tumors visible by MRI, H-1PV was instilled intranasally. Tumor regression was monitored by MRI, and survival was analyzed by Kaplan-Meier analysis. Brains from sacrificed animals were analyzed for histologic alterations, presence of viral DNA and proteins and infectious virions. In addition, distribution of virus to other organs was determined.
A single intranasal instillation of H-1PV was sufficient to induce efficient regression of rat glioma, leading to significant prolongation of survival without any toxicity for other tissues. It is shown that the virus reaches brain and other tissues, and that the viral replication-associated (and oncolysis-associated) regulatory proteins are exclusively expressed in the tumor tissue. In rats with xenografts of human glioma, oncolytic activity of H-1PV was less pronounced, however, leading to significant prolongation of survival.
In view of an ongoing clinical trial on the use of H-1PV for oncolytic virotherapy of glioma, the option of applying the virus intranasally may be a valuable alternative to invasive routes of infection.
在之前的研究中，我们已经表明，无致病的大鼠细小病毒 H-1（H-1PV）能够诱导大鼠模型中晚期有症状的大鼠和人神经胶质瘤的消退，当病毒被注射到肿瘤（脑内）或静脉内时。H-1PV 感染不会在非肿瘤组织中引起任何病理变化。本研究旨在探讨鼻内应用这种溶瘤病毒是否适合和足以治疗该动物模型中的神经胶质瘤。
大鼠（RG-2）或人（U87）神经胶质瘤细胞被立体定向植入大鼠脑内（分别为 Wistar 或 RNU），在 MRI 可见肿瘤发展后，将 H-1PV 鼻内滴注。通过 MRI 监测肿瘤消退，并用 Kaplan-Meier 分析分析生存情况。对处死动物的大脑进行组织学改变、病毒 DNA 和蛋白质以及感染性病毒粒子的存在分析。此外，还确定了病毒向其他器官的分布。
单次鼻内滴注 H-1PV 足以诱导大鼠神经胶质瘤的有效消退，导致生存时间显著延长，而对其他组织没有毒性。结果表明，病毒到达大脑和其他组织，并且病毒复制相关（和溶瘤相关）调节蛋白仅在肿瘤组织中表达。在人神经胶质瘤异种移植的大鼠中，H-1PV 的溶瘤活性不太明显，但导致生存时间显著延长。
鉴于正在进行的关于使用 H-1PV 进行神经胶质瘤溶瘤病毒治疗的临床试验，应用病毒鼻内给药可能是一种有价值的替代侵袭性感染途径的选择。
