Lun Xue Qing, Zhou Hongyuan, Alain Tommy, Sun Beichen, Wang Limei, Barrett John W, Stanford Marianne M, McFadden Grant, Bell John, Senger Donna L, Forsyth Peter A
Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada.
Cancer Res. 2007 Sep 15;67(18):8818-27. doi: 10.1158/0008-5472.CAN-07-1214.
We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model of human glioma. Here, we show that myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. Intratumoral injection of live myxoma virus when compared with control inactivated virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models [D341 median survival: 21 versus 12.5 days; P = 0.0008; Daoy median survival: not reached (three of five mice apparently "cured" after 223 days) versus 75 days; P = 0.0021]. Rapamycin increased the extent of viral oncolysis, "curing" most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice (median survival of mice treated with live virus (LV) and rapamycin, versus LV alone, versus rapamycin alone, versus inactivated virus: 25 days versus 19, 13, and 11 days, respectively; P < 0.0001). Rapamycin increased the levels of constitutively activated Akt in Daoy and D341 cells, which may explain its ability to enhance myxoma virus oncolysis. These observations suggest that myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.
我们之前已在人胶质瘤的小鼠异种移植模型中证明了黏液瘤病毒的溶瘤潜力。在此，我们表明，黏液瘤病毒单独使用或与雷帕霉素联合使用时，在髓母细胞瘤的体外和体内实验模型中均有效且安全。所测试的10种髓母细胞瘤细胞系中有9种易受致死性黏液瘤病毒感染，用雷帕霉素预处理细胞可增加体外溶瘤程度。在D341和Daoy原位人髓母细胞瘤异种移植小鼠模型中，与对照灭活病毒相比，瘤内注射活黏液瘤病毒可延长生存期[D341中位生存期：21天对12.5天；P = 0.0008；Daoy中位生存期：未达到（5只小鼠中有3只在223天后明显“治愈”）对75天；P = 0.0021]。雷帕霉素增加了病毒溶瘤程度，“治愈”了大多数携带Daoy肿瘤的小鼠，并减少或消除了脊髓和脑室转移。雷帕霉素增强了肿瘤特异性黏液瘤病毒在体内的复制，并延长了携带D341肿瘤小鼠的生存期（活病毒（LV）和雷帕霉素联合治疗的小鼠中位生存期，与单独LV、单独雷帕霉素、灭活病毒相比：分别为第25天对第19天、13天和11天；P < 0.0001）。雷帕霉素增加了Daoy和D341细胞中组成性激活的Akt水平，这可能解释了其增强黏液瘤病毒溶瘤作用的能力。这些观察结果表明，黏液瘤病毒可能是一种针对髓母细胞瘤的有效溶瘤剂，与调节磷脂酰肌醇3激酶/Akt途径活性的信号抑制剂联合治疗将进一步增强黏液瘤病毒的溶瘤潜力。
