Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer.
Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer.
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DOI：
10.1016/j.surg.2015.01.006
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发表时间：
2015-05
期刊：
影响因子：
3.8
通讯作者：
Davydova, Julia
中科院分区：
文献类型：
--
作者：
LaRocca, Christopher J.;Han, Joohee;Gavrikova, Tatyana;Armstrong, Leonard;Oliveira, Amanda R.;Shanley, Ryan;Vickers, Selwyn M.;Yamamoto, Masato;Davydova, Julia
在辅助放化疗方案中加入干扰素α（IFN）可显著改善胰腺癌患者的生存率。然而，全身毒性和肿瘤部位IFN水平不足限制了其在治疗方案中的广泛采用。我们先前已经开发了一种表达IFN的条件复制型溶瘤腺病毒，并在体外和体内证明了其治疗效果。在这里，相同的载体进行了测试，在同基因和免疫活性的叙利亚仓鼠模型，以更好地了解腺病毒复制和IFN的多效性对胰腺肿瘤生长抑制的作用。设计并产生表达人或仓鼠IFN的溶瘤腺病毒。在体外测试病毒载体以确定定性和定量的细胞活力、Cox2启动子活性和IFN产生。对于体内研究，用一个瘤内剂量的病毒处理皮下仓鼠胰腺癌肿瘤。类似地，一个腹膜内剂量的病毒用于延长癌病模型中的存活。所有测试的细胞系均表现出Cox2启动子活性。清楚地证明了表达IFN细胞因子的可复制腺病毒的溶瘤潜力。在仓鼠模型中，与对照组相比，这些病毒导致显著的肿瘤生长抑制和存活率增加。表达IFN的溶瘤腺病毒用于治疗胰腺癌的深刻治疗潜力在同基因叙利亚仓鼠模型中得到证实。这些结果有力地表明，我们的病毒作为与其他疗法的组合方案的一部分的潜在应用。
The addition of interferon alpha (IFN) to adjuvant chemoradiotherapy regimens resulted in remarkable improvements in survival for pancreatic cancer patients. However, systemic toxicities and insufficient levels of IFN at the tumor sites have limited its widespread adoption in treatment schemes. We have previously developed an IFN-expressing conditionally replicative oncolytic adenovirus and demonstrated its therapeutic effects both in vitro and in vivo. Here, the same vectors were tested in a syngeneic and immunocompetent Syrian hamster model to better understand the roles of adenoviral replication and of IFN’s pleiotropic effects on pancreatic tumor growth suppression. Oncolytic adenoviruses expressing human or hamster IFN were designed and generated. Viral vectors were tested in vitro to determine qualitative and quantitative cell viability, Cox2 promoter activity, and IFN production. For the in vivo studies, subcutaneous hamster pancreatic cancer tumors were treated with one intratumoral dose of virus. Similarly, one intraperitoneal dose of virus was used to prolong survival in a carcinomatosis model. All cell lines tested demonstrated Cox2 promoter activity. The oncolytic potential of a replication competent adenovirus expressing the IFN cytokine was clearly demonstrated. These viruses resulted in significant tumor growth suppression and survival increases compared to controls in a hamster model. The profound therapeutic potential of an IFN-expressing oncolytic adenovirus for the treatment of pancreatic cancer was demonstrated in a syngeneic Syrian hamster model. These results strongly suggest the potential application of our viruses as part of combination regimens with other therapeutics.
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