Oncolytic adenovirus armed with human papillomavirus E2 gene in combination with radiation demonstrates synergistic enhancements of antitumor efficacy
Oncolytic adenovirus armed with human papillomavirus E2 gene in combination with radiation demonstrates synergistic enhancements of antitumor efficacy
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携带人乳头瘤病毒E2基因的溶瘤腺病毒与放射组合显示出协同增强的抗肿瘤功效
DOI：
10.1038/cgt.2011.53
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发表时间：
2011-11
影响因子：
6.4
通讯作者：
D. Ma
中科院分区：
文献类型：
--
作者：
W. Wang, X. Xia, S. Wang, N. Sima, Y. Li, Z. Han,;D. Ma
高危型人乳头瘤病毒（hr-HPV）E6和E7癌基因与宫颈癌放疗抵抗相关。已经努力采用HPV E2（HPV E6和E7癌基因的关键负转录调节剂，也是一种增殖诱导剂）用于治疗干预。尽管在概念上有吸引力，但目前基于hr-HPV E2的疗法的效力和可行性仍然有限。本研究设计了一种新型的重组腺病毒M5，该腺病毒在E1 A保守区2缺失27个碱基，实现了肿瘤特异性复制，并在E3编码区插入了完整的HPV 16型（HPV 16）E2基因互补DNA。在该设计中，M5利用腺病毒E3启动子以病毒复制依赖的方式表达HPV 16 E2基因，并优先沉默HPV阳性宫颈癌细胞中的hr-HPV E6和E7癌基因。在体外和体内试验证实，M5表现出强大的抗肿瘤疗效。此外，M5和辐射处理的组合处理的效果导致协同增强的效力（P< 0.01）。在HPV阴性宫颈癌细胞中也发现了M5杀伤效力的增加，因此HPV 16 E2的促凋亡活性是其原因。我们的研究结果表明，使用M5局部递送HPV 16 E2至癌症具有广泛的治疗窗口，并且宫颈癌的放射联合治疗将是提高生存率的更有效方法。
High-risk human papillomavirus (hr-HPV) E6 and E7 oncogenes are associated with resistance to radiotherapy in cervical cancer. Efforts have been taken to employ HPV E2, a crucial negative transcriptional modulator of HPV E6 and E7 oncogenes, and also an apoptosis-inducing agent, for therapeutic intervention. Despite being conceptually attractive, the potency and feasibility of current hr-HPV E2-based therapies remain limited. Here, we designed a novel recombinant adenovirus, named M5, with a 27-bp deletion in E1A conserved region-2 by which to realize tumor-specific replication, and a total HPV type 16 (HPV16) E2 gene complementary DNA inserted into the E3 coding region. In this design, M5 exploited the adenovirus E3 promoters to express HPV16 E2 gene in a viral replication-dependent manner and preferentially silenced the hr-HPV E6 and E7 oncogenes in HPV-positive cervical cancer cells. In vitro and in vivo assays confirmed that M5 exhibited potent antitumoral efficacy. Moreover, the effects of combined treatment with M5 and radiation treatment resulted in synergistically enhanced potency (P< 0.01). The increase in killing efficacy of M5 was also found in HPV-negative cervical cancer cells, for which the pro-apoptotic activity of HPV16 E2 was thus responsible. Our results indicated that the use of M5 that locally delivers HPV16 E2 to cancers has broad therapeutic windows and that the combination therapy with radiation for cervical cancer will be the more effective way of improving survival.
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影响因子：
--
作者：
De-chao Yu;P. Working;D. Ando
通讯作者：
De-chao Yu;P. Working;D. Ando
DOI：
10.1074/jbc.275.1.87
发表时间：
2000-01
期刊：
The Journal of Biological Chemistry
影响因子：
--
作者：
K. Webster;Joanna L. Parish;Maya Pandya;P. Stern;A. Clarke;K. Gaston
通讯作者：
K. Webster;Joanna L. Parish;Maya Pandya;P. Stern;A. Clarke;K. Gaston
影响因子：
9.7
作者：
Wei Wang;Ni Sima;Debo Kong;A. Luo;Q. Gao;Shujie Liao;Wei Li;Ling-fei Han;Juan Wang;
通讯作者：
Wei Wang;Ni Sima;Debo Kong;A. Luo;Q. Gao;Shujie Liao;Wei Li;Ling-fei Han;Juan Wang;
影响因子：
1.3
作者：
S. Bhosle;N. Huilgol;K. Mishra
通讯作者：
S. Bhosle;N. Huilgol;K. Mishra
影响因子：
11.2
作者：
Jian Zhou;B. Gurates;Sijun Yang;Siby Sebastian;S. Bulun
通讯作者：
Jian Zhou;B. Gurates;Sijun Yang;Siby Sebastian;S. Bulun