6月15日，PLoS ONE在線報(bào)道了缺氧調(diào)節(jié)溶瘤腺病毒治療腫瘤的研究進(jìn)展,。缺氧是一個(gè)微環(huán)境因素,，有助于腫瘤細(xì)胞的侵襲，進(jìn)展和轉(zhuǎn)移,。缺氧腫瘤細(xì)胞往往會(huì)比常氧腫瘤細(xì)胞表現(xiàn)出更大的放化療抵抗能力,。這表明人類需要新型抗癌療法有效地消除缺氧腫瘤細(xì)胞。
以往研究發(fā)明了腫瘤特異的復(fù)制性溶瘤腺病毒（OBP-301：Telomelysin）,。其中,，人端粒酶逆轉(zhuǎn)錄酶（hTERT）啟動(dòng)子驅(qū)動(dòng)病毒E1的表達(dá)。 hTERT基因啟動(dòng)子活性已經(jīng)被證明可被缺氧所上調(diào),。研究者由此推測(cè),，在缺氧條件下，具有hTERT啟動(dòng)子的OBP-301腺病毒的抗腫瘤效率將高于野生型5型腺病毒（AD5）,。
本研究比較了OBP-301和Ad5在常氧（20％氧）或缺氧（1％的氧氣）條件下對(duì)人類癌細(xì)胞的抗腫瘤作用,。低氧條件促進(jìn)缺氧誘導(dǎo)因子-1α在細(xì)胞核積累，并上調(diào)人類癌細(xì)胞中hTERT啟動(dòng)子活性。缺氧條件下OBP-301的溶瘤效果明顯比Ad5高,。與溶瘤效果相一致的是,，OBP-301復(fù)制能力在缺氧條件下也高于Ad5。
在人類異種移植瘤模型小鼠腫瘤的缺氧區(qū)域內(nèi),，研究者檢測(cè)到了OBP-301介導(dǎo)的E1A表達(dá),。
這些結(jié)果表明，OBP-301對(duì)缺氧的腫瘤細(xì)胞的溶瘤效應(yīng)是缺氧激活hTERT啟動(dòng)子介導(dǎo)的,。溶瘤腺病毒hTERT啟動(dòng)子的調(diào)控,，是一個(gè)有前途的抗癌戰(zhàn)略。它不僅誘導(dǎo)腫瘤特異性溶瘤,，同時(shí)也高效清除缺氧的腫瘤細(xì)胞,。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
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.
