Combination of the oncolytic adenovirus ICOVIR-5 with chemotherapy provides enhanced anti-glioma effect in vivo
Combination of the oncolytic adenovirus ICOVIR-5 with chemotherapy provides enhanced anti-glioma effect in vivo
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DOI：
10.1038/sj.cgt.7701067
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发表时间：
2007-08-01
影响因子：
6.4
通讯作者：
Fueyo, J.
中科院分区：
文献类型：
--
作者：
Alonso, M. M.;Gomez-Manzano, C.;Fueyo, J.
神经胶质瘤显然需要新的治疗方法，溶瘤载体与化疗的组合具有治疗这种恶性肿瘤的重大希望。此外，与化疗组合允许较低的病毒剂量以实现抗癌作用，从而导致较低的由于病毒蛋白引起的不良毒性。在这项工作中，我们试图确定溶瘤腺病毒ICOVIR-5与RAD 001或替莫唑胺（TMZ）的组合是否可以导致体内增强的抗胶质瘤作用。我们分别通过MTT和TCID 50评估了ICOVIR-5与RAD 001或TMZ组合在U87 MG胶质瘤细胞系中的体外细胞毒性效应和复制特性。我们的数据表明，在体外治疗RAD 001或TMZ不仅干扰腺病毒复制，但此外，增强其溶瘤性能。为评价体内抗癌作用，荷胶质瘤异种移植物（5 × 10（5）U87 MG细胞/动物）的无胸腺小鼠接受单次瘤内注射ICOVIR-5（10（7）PFU/动物）。以每周5天5 mg/kg的方案给予RAD 001直至实验结束，并以7.5mg/kg/小鼠的剂量给予TMZ 5天。重要的是，ICOVIR-5与RAD 001或TMZ的组合显示出有效的体内抗胶质瘤作用，导致中值动物存活的显著延长，并且20-40%的动物在超过90天后变得无疾病。
Novel therapies are clearly needed for gliomas, and the combination of oncolytic vectors with chemotherapy possesses a significant hope for the treatment of this malignancy. In addition, combination with chemotherapy allows for lower virus doses to achieve anticancer effect, thus resulting in lower undesirable toxicities due to viral proteins. In this work, we sought to determine whether combination of an oncolytic adenovirus ICOVIR-5, with RAD001 or temozolomide (TMZ) could result in enhanced anti-glioma effect in vivo. We assessed the in vitro cytotoxic effect and replication properties of ICOVIR-5 in combination with RAD001 or TMZ in U87 MG glioma cell line by MTT and TCID50, respectively. Our data showed that in vitro treatment with RAD001 or TMZ not only interfered with adenovirus replication but, in addition, enhanced its oncolytic properties. To evaluate the in vivo anticancer effect, athymic mice bearing glioma xenografts (5 x 10(5) U87 MG cells/animal) received a single intratumoral injection of ICOVIR-5 (10(7) PFU/animal). RAD001 was given as a regimen of 5 mg/kg 5 days per week until the end of the experiment and TMZ was administered for 5 days at 7.5 mg/kg/mice. Of significance, combination of ICOVIR-5 with RAD001 or TMZ showed a potent antiglioma effect in vivo, resulting in a dramatic extension of the median animal survival and in 20-40% animals becoming free of disease beyond 90 days.