The Bioreductive Prodrug PR-104A Is Activated under Aerobic Conditions by Human Aldo-Keto Reductase 1C3
The Bioreductive Prodrug PR-104A Is Activated under Aerobic Conditions by Human Aldo-Keto Reductase 1C3
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DOI：
10.1158/0008-5472.can-09-3237
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Patterson, Adam V.
中科院分区：
文献类型：
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作者：
Guise, Christopher P.;Abbattista, Maria R.;Patterson, Adam V.
PR-104目前处于第二阶段临床试验，是一种磷酸酯前药，在体内可转化为其同源酒精PR-104A，这是一种旨在利用肿瘤缺氧的前药。在无氧条件下，生物活化通过单电子还原为DNA交联代谢物而发生。然而，某些肿瘤细胞系在氧气存在的情况下激活PR-104A，这表明存在一种好氧硝基还原酶。基因芯片分析鉴定了5个醛酮还原酶(AKR)家族成员，其表达与PR-104A的有氧代谢相关。以质粒为基础表达的候选基因鉴定为一种新的亚硝酸还原酶。在23个细胞系中，有7个细胞系中检测到AKR1C3蛋白，并与PR-104A氧化代谢相关，这种活性可被Nrf2 RNAi敲除部分抑制(或被Keap1 RNAi诱导)，表明Are途径对AKR1C3蛋白的调节。AKR1C3不能使细胞对其他10种生物还原前体药物敏感，并且与9种人类肿瘤异种移植模型中的单剂PR-104活性有关。在两个AKR1C3阴性的肿瘤移植模型中过表达显著增强PR-104的抗肿瘤活性。使用组织微阵列对19种癌症类型的2490例个体进行的人群水平调查显示，AKR1C3在包括肝细胞癌、膀胱癌、肾癌、胃癌和非小细胞肺癌在内的一个亚群中显著上调。一项对正常组织AKR1C3表达的调查表明，通过这一机制有可能激活肿瘤选择性PR-104A。这些发现对PR-104的临床开发具有重要意义。癌症资源；70(4)；1573-84年。(C)2010年AACR。
PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell lines activate PR-104A in the presence of oxygen, suggesting the existence of an aerobic nitroreductase. Microarray analysis identified a cluster of five aldo-keto reductase (AKR) family members whose expressions correlated with aerobic metabolism of PR-104A. Plasmid-based expression of candidate genes identified aldo-keto reductase 1C3 as a novel nitroreductase. AKR1C3 protein was detected by Western blot in 7 of 23 cell lines and correlated with oxic PR-104A metabolism, an activity which could be partially suppressed by Nrf2 RNAi knockdown (or induced by Keap1 RNAi), indicating regulation by the ARE pathway. AKR1C3 was unable to sensitize cells to 10 other bioreductive prodrugs and was associated with single-agent PR-104 activity across a panel of 9 human tumor xenograft models. Overexpression in two AKR1C3-negative tumor xenograft models strongly enhanced PR-104 antitumor activity. A population level survey of AKR1C3 expression in 2,490 individual cases across 19 cancer types using tissue microarrays revealed marked upregulation of AKR1C3 in a subset including hepatocellular, bladder, renal, gastric, and non-small cell lung carcinoma. A survey of normal tissue AKR1C3 expression suggests the potential for tumor-selective PR-104A activation by this mechanism. These findings have significant implications for the clinical development of PR-104. Cancer Res; 70(4); 1573-84. (C) 2010 AACR.