Pharmacologically increased tumor hypoxia can be measured by 18F-Fluoroazomycin arabinoside positron emission tomography and enhances tumor response to hypoxic cytotoxin PR-104.
Pharmacologically increased tumor hypoxia can be measured by 18F-Fluoroazomycin arabinoside positron emission tomography and enhances tumor response to hypoxic cytotoxin PR-104.
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DOI：
10.1158/1078-0432.ccr-09-1676
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Denko NC
中科院分区：
文献类型：
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作者：
Cairns RA;Bennewith KL;Graves EE;Giaccia AJ;Chang DT;Denko NC
实体瘤含有缺氧的微环境区域，对传统的放疗和化疗构成障碍，这项工作描述了一种规避缺氧的新方法。我们建议通过增强专为杀死缺氧肿瘤细胞而设计的药物的有效性来克服缺氧。我们已经构建了RKO结直肠肿瘤细胞，其表达特异性敲低缺氧诱导因子1a（HIF 1a）转录因子的小RNA发夹。我们已经使用这些细胞在体外，以确定HIF 1对细胞的缺氧细胞毒素PR-104的敏感性的影响，以及其在细胞耗氧量响应丙酮酸脱氢酶激酶抑制剂二氯乙酸（DCA）的作用。我们进一步在异种移植肿瘤中使用这些细胞，以确定HIF 1在调节肿瘤缺氧中的作用，以响应使用18 F-氟偶氮霉素阿糖甙正电子发射断层扫描DCA，其在调节肿瘤的敏感性DCA和PR-104的组合的作用。HIF 1不影响细胞对PR-104的体外敏感性。DCA瞬时增加体外细胞耗氧量，并增加体内肿瘤缺氧的程度，如18F-氟偶氮霉素阿拉伯糖苷正电子发射断层扫描所测量的。此外，我们表明，DCA依赖性改变缺氧增加下一代缺氧细胞毒素PR-104的抗肿瘤活性。DCA干扰HIF依赖的“适应性反应”，限制线粒体耗氧量。这种方法瞬时增加肿瘤缺氧，代表了改善缺氧靶向药物的抗肿瘤功效的重要方法，而不会增加对含氧正常组织的毒性。
Solid tumors contain microenvironmental regions of hypoxia that present a barrier to traditional radiotherapy and chemotherapy, and this work describes a novel approach to circumvent hypoxia. We propose to overcome hypoxia by augmenting the effectiveness of drugs that are designed to specifically kill hypoxic tumor cells. We have constructed RKO colorectal tumor cells that express a small RNA hairpin that specifically knocks down the hypoxia-inducible factor 1a (HIF1a) transcription factor. We have used these cells in vitro to determine the effect of HIF1 on cellular sensitivity to the hypoxic cytotoxin PR-104, and its role in cellular oxygen consumption in response to the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA). We have further used these cells in vivo in xenografted tumors to determine the role of HIF1 in regulating tumor hypoxia in response to DCA using 18F-fluoroazomycin arabinoside positron emission tomography, and its role in regulating tumor sensitivity to the combination of DCA and PR-104. HIF1 does not affect cellular sensitivity to PR-104 in vitro. DCA transiently increases cellular oxygen consumption in vitro and increases the extent of tumor hypoxia in vivo as measured with 18F-fluoroazomycin arabinoside positron emission tomography. Furthermore, we show that DCA-dependent alterations in hypoxia increase the antitumor activity of the next-generation hypoxic cytotoxin PR-104. DCA interferes with the HIF-dependent “adaptive response,” which limits mitochondrial oxygen consumption. This approach transiently increases tumor hypoxia and represents an important method to improve antitumor efficacy of hypoxia-targeted agents, without increasing toxicity to oxygenated normal tissue.