Enhanced antitumor effect of combined replicative adenovirus and nonreplicative adenovirus expressing interleukin-12 in an immunocompetent mouse model
Enhanced antitumor effect of combined replicative adenovirus and nonreplicative adenovirus expressing interleukin-12 in an immunocompetent mouse model
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DOI：
10.1038/sj.gt.3302001
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发表时间：
2003-08-01
期刊：
影响因子：
5.1
通讯作者：
Niwa, M
中科院分区：
文献类型：
--
作者：
Nagayama, Y;Nakao, K;Niwa, M
对于癌症基因治疗，复制型腺病毒是一种很有前景的载体，可以克服非复制型腺病毒体内感染性低和基因传递能力差的问题，但由于复制型病毒在实体瘤中的传播有限，其治疗效果仍然不令人满意。因此，与其他抗肿瘤药物的联合治疗可能是必要的。表达治疗基因的非复制性腺病毒可能是有前途的候选者，因为复制性腺病毒表达的E1蛋白将使非复制性腺病毒具有复制性，增强转基因表达。在这项研究中，我们首先发现小鼠肝癌Hepa 1-6细胞允许人腺病毒的复制和细胞病变效应，这使我们能够在免疫活性小鼠同基因Hepa 1-6肿瘤模型中研究联合复制型腺病毒和非复制型腺病毒表达免疫刺激剂的潜力。使用表达白细胞介素 12 (AdIL-12) 的非复制腺病毒作为模型。在该细胞系中，两种腺病毒的体外共感染产生的 IL-12 浓度比单独感染 AdIL-12 更高。在同基因免疫活性 C57BL/6 小鼠中对 Hepa 1-6 肿瘤进行的体内实验显示，与任一腺病毒感染相比，联合治疗中血清 IL-12 浓度更高，治疗效果也更好。这些数据表明，复制型腺病毒和表达免疫刺激剂的非复制型腺病毒的组合对于癌症基因治疗似乎非常有效。
For cancer gene therapy, replicative adenovirus is a promising vector to overcome low infectivity and poor gene delivery of nonreplicative adenovirus in vivo, but its therapeutic efficacy is still unsatisfactory because of the limited spread of replicative virus in a solid tumor. Therefore, the combined therapy with other antitumor agents may be necessary. Nonreplicative adenovirus expressing a therapeutic gene may be a promising candidate because El proteins expressed by replicative adenovirus would render nonreplicative adenovirus replicative, augmenting a transgene expression. In this study, we first found that mouse hepatoma Hepa 1-6 cells were permissive for the replication and cytopathic effect of human adenovirus, which enabled us to examine the potential of combined replicative adenovirus and nonreplicative adenovirus expressing an immunostimulator in an immunocompetent mouse-syngeneic Hepa 1-6 tumor model. Nonreplicative adenovirus expressing interleukin-12 (AdIL-12) was used as a model. In vitro coinfection of two adenoviruses produced higher concentrations of IL-12 than infection of AdIL-12 alone in this cell line. In vivo experiments with Hepa 1-6 tumors in syngeneic immunocompetent C57BL/6 mice showed higher concentrations of serum IL-12 and greater therapeutic efficacy in the combination therapy than infection of either adenovirus. These data indicate that the combination of replicative adenovirus and nonreplicative adenovirus expressing an immunostimulator appears to be very efficacious for cancer gene therapy.