Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy
Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy
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DOI：
10.1016/j.amjsurg.2012.02.016
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发表时间：
2012-11-01
影响因子：
3
通讯作者：
Davydova, Julia
中科院分区：
文献类型：
--
作者：
Armstrong, Leonard;Arrington, Amanda;Davydova, Julia
背景：溶瘤腺病毒为癌症治疗提供了一种有前途的选择。最近，辅助干扰素（IFN）-α已显示出胰腺癌的显著生存益处，但受到全身毒性的阻碍。为了避免这些问题，可以产生具有高水平靶向IFN-α表达的腺病毒。方法：产生对胰腺癌具有改善的毒力和选择性的连续复制型腺病毒（CRAds）。载体进行了测试，在体外，在体内，并在人胰腺癌和正常组织samples.RESULTS：腺病毒死亡蛋白和纤维的修改显着提高溶瘤。CRAds在体外、体内选择性复制，并在癌症异种移植物中表现出持续扩散。他们在人类胰腺癌标本中表现出高水平的复制，但在正常组织中没有。结论：优化的环氧合酶-2 CRAds在体外和体内显示出非常有利的效果。我们报道了一种胰腺癌特异性、高毒力、表达IFN的CRAd，我们相信基于腺病毒的IFN治疗为胰腺癌患者提供了一个新的治疗机会。(C)2012 Elsevier Inc. All rights reserved.
BACKGROUND: Oncolytic adenoviruses provide a promising alternative for cancer treatment. Recently, adjuvant interferon (IFN)-alfa has shown significant survival benefits for pancreatic cancer, yet was impeded by systemic toxicity. To circumvent these problems adenovirus with high-level targeted IFN-alfa expression can be generated.METHODS: Conditionally replicative adenoviruses (CRAds) with improved virulence and selectivity for pancreatic cancer were generated. The vectors were tested in vitro, in vivo, and in human pancreatic cancer and normal tissue specimens.RESULTS: Adenoviral death protein and fiber modifications significantly improved oncolysis. CRAds selectively replicated in vitro, in vivo and showed persistent spread in cancer xenografts. They showed high-level replication in human pancreatic cancer specimens, but not in normal tissues. Improved IFN-CRAd oncolytic efficiency was shown.CONCLUSIONS: Optimized cyclooxygenase-2 CRAds show highly favorable effects in vitro and in vivo. We report a pancreatic cancer-specific, highly virulent, IFN-expressing CRAd, and we believe that adenovirus-based IFN therapy offers a new treatment opportunity for pancreatic cancer patients. (C) 2012 Elsevier Inc. All rights reserved.