PLoS ONE:缺氧调节的溶瘤腺病毒基因治疗

6月15日，PLoS ONE在线报道了缺氧调节溶瘤腺病毒治疗肿瘤的研究进展。缺氧是一个微环境因素，有助于肿瘤细胞的侵袭，进展和转移。缺氧肿瘤细胞往往会比常氧肿瘤细胞表现出更大的放化疗抵抗能力。这表明人类需要新型抗癌疗法有效地消除缺氧肿瘤细胞。

以往研究发明了肿瘤特异的复制性溶瘤腺病毒（OBP-301：Telomelysin）。其中，人端粒酶逆转录酶（hTERT）启动子驱动病毒E1的表达。 hTERT基因启动子活性已经被证明可被缺氧所上调。研究者由此推测，在缺氧条件下，具有hTERT启动子的OBP-301腺病毒的抗肿瘤效率将高于野生型5型腺病毒（AD5）。

本研究比较了OBP-301和Ad5在常氧（20％氧）或缺氧（1％的氧气）条件下对人类癌细胞的抗肿瘤作用。低氧条件促进缺氧诱导因子-1α在细胞核积累，并上调人类癌细胞中hTERT启动子活性。缺氧条件下OBP-301的溶瘤效果明显比Ad5高。与溶瘤效果相一致的是，OBP-301复制能力在缺氧条件下也高于Ad5。
在人类异种移植瘤模型小鼠肿瘤的缺氧区域内，研究者检测到了OBP-301介导的E1A表达。

这些结果表明，OBP-301对缺氧的肿瘤细胞的溶瘤效应是缺氧激活hTERT启动子介导的。溶瘤腺病毒hTERT启动子的调控，是一个有前途的抗癌战略。它不仅诱导肿瘤特异性溶瘤，同时也高效清除缺氧的肿瘤细胞。

doi:10.1016/j.cell.2011.10.017
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The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment

Yuuri Hashimoto1, Hiroshi Tazawa1,2, Fuminori Teraishi1, Toru Kojima1, Yuichi Watanabe1, Futoshi Uno1, Shuya Yano1, Yasuo Urata3, Shunsuke Kagawa1, Toshiyoshi Fujiwara

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.