Wilcox M E, Yang W, Senger D, Rewcastle N B, Morris D G, Brasher P M, Shi Z Q, Johnston R N, Nishikawa S, Lee P W, Forsyth P A
Departments of Oncology and Clinical Neurosciences, University of Calgary, and Tom Baker Cancer Centre, Alberta, Canada.
J Natl Cancer Inst. 2001 Jun 20;93(12):903-12. doi: 10.1093/jnci/93.12.903.
Reovirus is a naturally occurring oncolytic virus that usurps activated Ras-signaling pathways of tumor cells for its replication. Ras pathways are activated in most malignant gliomas via upstream signaling by receptor tyrosine kinases. The purpose of this study was to determine the effectiveness of reovirus as an experimental treatment for malignant gliomas.
We investigated whether reovirus would infect and lyse human glioma cell lines in vitro. We also tested the effect of injecting live reovirus in vivo on human gliomas grown subcutaneously or orthotopically (i.e., intracerebrally) in mice. Finally, reovirus was tested ex vivo against low-passage cell lines derived from human glioma specimens. All P values were two-sided.
Reovirus killed 20 (83%) of 24 established malignant glioma cell lines tested. It caused a dramatic and often complete tumor regression in vivo in two subcutaneous (P =.0002 for both U251N and U87) and in two intracerebral (P =.0004 for U251N and P =.0009 for U87) human malignant glioma mouse models. As expected, serious toxic effects were found in these severely immunocompromised hosts. In a less immunocompromised mouse model, a single intratumoral inoculation of live reovirus led to a dramatic prolongation of survival (compared with control mice treated with dead virus; log-rank test, P<.0001 for both U251N and U87 cell lines). The animals treated with live virus also appeared to be healthier and gained body weight (P =.0001). We then tested the ability of reovirus to infect and kill primary cultures of brain tumors removed from patients and found that it killed nine (100%) of nine glioma specimens but none of the cultured meningiomas.
Reovirus has potent activity against human malignant gliomas in vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.
呼肠孤病毒是一种天然存在的溶瘤病毒，它利用肿瘤细胞激活的Ras信号通路进行复制。在大多数恶性胶质瘤中，Ras通路通过受体酪氨酸激酶的上游信号传导而被激活。本研究的目的是确定呼肠孤病毒作为恶性胶质瘤实验性治疗方法的有效性。
我们研究了呼肠孤病毒在体外是否会感染并裂解人胶质瘤细胞系。我们还测试了在体内注射活呼肠孤病毒对在小鼠皮下或原位（即脑内）生长的人胶质瘤的影响。最后，对从人胶质瘤标本中获得的低传代细胞系进行了呼肠孤病毒的体外测试。所有P值均为双侧。
呼肠孤病毒杀死了所测试的24种已建立的恶性胶质瘤细胞系中的20种（83%）。在两种皮下（U251N和U87的P值均为0.0002）和两种脑内（U251N的P值为0.0004，U87的P值为0.0009）人恶性胶质瘤小鼠模型中，它在体内引起了显著且通常是完全的肿瘤消退。正如预期的那样，在这些严重免疫受损的宿主中发现了严重的毒性作用。在免疫受损较轻的小鼠模型中，单次瘤内接种活呼肠孤病毒导致生存期显著延长（与用灭活病毒治疗的对照小鼠相比；对数秩检验，U251N和U87细胞系的P值均<0.0001）。用活病毒治疗的动物似乎也更健康且体重增加（P = 0.0001）。然后我们测试了呼肠孤病毒感染并杀死从患者身上切除的脑肿瘤原代培养物的能力，发现它杀死了9种胶质瘤标本中的9种（100%），但未杀死任何培养的脑膜瘤。
呼肠孤病毒在体外、体内和体外对人恶性胶质瘤均具有强大的活性。用呼肠孤病毒进行溶瘤可能是一种对多种人类癌症潜在有用的治疗方法。
