Adenovirus-mediated hypoxia-targeting cytosine deaminase gene therapy enhances radiotherapy in tumour xenografts.
Adenovirus-mediated hypoxia-targeting cytosine deaminase gene therapy enhances radiotherapy in tumour xenografts.
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DOI：
10.1038/sj.bjc.6603812
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发表时间：
2007-06-18
影响因子：
8.8
通讯作者：
Hiraoka, M.
中科院分区：
文献类型：
--
作者：
Liu, J.;Harada, H.;Ogura, M.;Shibata, T.;Hiraoka, M.
关键词：
缺氧与肿瘤的放射抗性密切相关，因此，靶向缺氧区域对于癌症治疗非常重要。本研究的目的是建立这样的靶向策略，通过应用细菌胞嘧啶脱氨酶（BCD）/5-氟胞嘧啶（5-FC）基因治疗系统，并检查该策略是否提高放射治疗在肿瘤异种移植物的疗效。低氧应答启动子5 HREp，其中5个拷贝的低氧应答元件（HRE）增强从巨细胞病毒最小启动子的转录，被用来诱导BCD在低氧条件下的表达。腺病毒载体Ad/5 HREp-BCD，编码基因5 HREp-BCD，在缺氧条件下强烈诱导BCD表达，这导致了显着的细胞毒性与5-FC在体外组合。瘤内Ad/5 HREp-BCD给药导致BCD在含氧量正常和坏死区域之间的边界处表达。BCD/5-FC基因治疗增强了单次（12.5戈伊）和分次（3戈伊× 5天）放疗的疗效，副作用少，肿瘤生长倍增时间分别增加了2.4倍（P<0.01）和2.5倍（P<0.05）。所有这些结果表明，目前的BCD/5-FC基因治疗具有特异性靶向缺氧肿瘤细胞的能力，并显着改善放疗后肿瘤生长的控制。
Hypoxia is closely associated with the radioresistance of tumours; therefore, targeting hypoxic areas is very important for cancer therapy. The aim of this study is to establish such a targeting strategy by applying a bacterial cytosine deaminase (BCD)/5-fluorocytosine (5-FC) gene therapy system and to examine whether the strategy enhances the efficacy of radiotherapy in a tumour xenograft. The hypoxia-responsive promoter 5HREp, in which five copies of the hypoxia-response element (HRE) enhance transcription from a cytomegalovirus minimal promoter, was employed to induce the expression of BCD under hypoxic conditions. The adenoviral vector Ad/5HREp-BCD, encoding the gene 5HREp-BCD, robustly induced BCD expression under hypoxic conditions and this led to significant cytotoxicity in combination with 5-FC in vitro. Intratumoral Ad/5HREp-BCD administration resulted in the expression of BCD at the border between normoxic and necrotic regions. The BCD/5-FC gene therapy enhanced the therapeutic effects of both single (12.5 Gy) and fractionated (3 Gy × 5 days) radiotherapy with few side effects and significantly increased tumour growth doubling time by up to 2.4-fold (P<0.01) and 2.5-fold (P<0.05), respectively. All of these results suggest that the present BCD/5-FC gene therapy has the ability to specifically target hypoxic tumour cells and significantly improves the control of tumour growth after radiotherapy.
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