The hTERT promoter enhances the antitumor activity of an oncolytic adenovirus under a hypoxic microenvironment.
The hTERT promoter enhances the antitumor activity of an oncolytic adenovirus under a hypoxic microenvironment.
复制标题
DOI：
10.1371/journal.pone.0039292
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Fujiwara T
中科院分区：
文献类型：
--
作者：
Hashimoto Y;Tazawa H;Teraishi F;Kojima T;Watanabe Y;Uno F;Yano S;Urata Y;Kagawa S;Fujiwara T
缺氧是肿瘤细胞侵袭、发展和转移的微环境因素。低氧肿瘤细胞通常比常氧肿瘤细胞对常规放化疗显示出更大的抗性，这表明需要新的抗肿瘤疗法来有效地消除低氧肿瘤细胞。我们以前产生了肿瘤特异性复制能力溶瘤腺病毒（OBP-301：端粒溶素），其中人端粒酶逆转录酶（hTERT）启动子驱动病毒E1的表达。由于hTERT基因的启动子活性已被证明是由缺氧上调，我们假设，在缺氧条件下，OBP-301与hTERT启动子的抗肿瘤效果将是更有效的比野生型腺病毒5（Ad 5）。在这项研究中，我们研究了OBP-301和Ad 5在常氧（20%氧气）和低氧（1%氧气）条件下对人癌细胞的抗肿瘤作用。低氧条件诱导人癌细胞中低氧诱导因子-1 α的核积聚和hTERT启动子活性的上调缺氧条件下OBP-301的细胞病变活性显著高于Ad 5。与它们的细胞病变活性一致，在缺氧条件下，OBP-301的复制显著高于Ad 5。OBP-301介导的E1 A在小鼠人异种移植肿瘤的缺氧区域内表达。这些结果表明，OBP-301对缺氧肿瘤细胞的致细胞病变活性是通过缺氧介导的hTERT启动子激活介导的。通过hTERT启动子调节溶瘤腺病毒是一种有前途的抗肿瘤策略，不仅用于诱导肿瘤特异性溶瘤，而且用于有效消除缺氧肿瘤细胞。
Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1α and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.
登录
查看更多内容
影响因子：
50.3
作者：
Chang CJ;Yang JY;Xia W;Chen CT;Xie X;Chao CH;Woodward WA;Hsu JM;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
8
作者：
Anderson, CJ;Hoare, SF;Keith, WN
通讯作者：
Keith, WN
影响因子：
5.3
作者：
Nishi, H;Nakada, T;Isaka, K
通讯作者：
Isaka, K
影响因子：
11.5
作者：
Castelo-Branco, Pedro;Zhang, Cindy;Tabori, Uri
通讯作者：
Tabori, Uri
影响因子：
11.5
作者：
Kwon, Oh-Joon;Kim, Pyung-Hwan;Yun, Chae-Ok
通讯作者：
Yun, Chae-Ok