Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice
Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice
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DOI：
10.1007/s00280-010-1354-5
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发表时间：
2011-03-01
影响因子：
3
通讯作者：
Wilson, William R.
中科院分区：
文献类型：
--
作者：
Gu, Yongchuan;Guise, Christopher P.;Wilson, William R.
PR-104是一种临床试验中的生物还原前药，是一种磷酸酯，可迅速代谢为相应的醇PR-104 A。这种二硝基苯甲酰胺芥子气通过在缺氧细胞中选择性还原为羟胺（PR-104 H）和胺（PR-104 M）代谢物而被激活，并且在某些肿瘤中也不依赖于醛酮还原酶（AKR）1C 3的缺氧。在此，我们评估了PR-104 A在小鼠中的还原代谢及其对宿主毒性的意义。在小鼠血浆和组织中研究PR-104 A及其还原代谢产物药代动力学研究鉴定了PR-104 A对5-羟色胺的广泛的非肿瘤减少（有和没有SiHa或H460肿瘤异种移植物）和潜在的氧化还原酶抑制剂的作用。胺PR-104 H（其身份已通过化学合成证实），尤其是在肝脏中。然而，表明肿瘤内活化的肿瘤中PR-104 H的高浓度也是显著的。PR-104 M/H的组织分布与PR-104的靶器官毒性（骨髓、肠和肝脏）大致一致。令人惊讶的是，当通过肝动脉结扎或呼吸10%的氧气使肝脏缺氧时，肝脏的硝基还原并没有增强。一项非甾体抗炎药筛选发现，在人类肿瘤细胞培养物和异种移植物中，萘普生是一种有效的AKR 1C 3抑制剂，这表明它可能用于改善患者的PR-104毒性。然而，无论是萘普生还是泛磷酸酶抑制剂1-氨基苯并三唑都不能抑制小鼠中PR-104 A的正常组织还原。PR-104在小鼠组织中被广泛还原，显然是通过氧非依赖性双电子还原，其组织分布广泛反映了毒性。
PR-104, a bioreductive prodrug in clinical trial, is a phosphate ester which is rapidly metabolized to the corresponding alcohol PR-104A. This dinitrobenzamide mustard is activated by reduction to hydroxylamine (PR-104H) and amine (PR-104M) metabolites selectively in hypoxic cells, and also independently of hypoxia by aldo-keto reductase (AKR) 1C3 in some tumors. Here, we evaluate reductive metabolism of PR-104A in mice and its significance for host toxicity.The pharmacokinetics of PR-104, PR-104A and its reduced metabolites were investigated in plasma and tissues of mice (with and without SiHa or H460 tumor xenografts) and effects of potential oxidoreductase inhibitors were evaluated.Pharmacokinetic studies identified extensive non-tumor reduction of PR-104A to the 5-amine PR-104H (identity of which was confirmed by chemical synthesis), especially in liver. However, high concentrations of PR-104H in tumors that suggested intra-tumor activation is also significant. The tissue distribution of PR-104M/H was broadly consistent with the target organ toxicities of PR-104 (bone marrow, intestines and liver). Surprisingly, hepatic nitroreduction was not enhanced when the liver was made more hypoxic by hepatic artery ligation or breathing of 10% oxygen. A screen of non-steroidal anti-inflammatory drugs identified naproxen as an effective AKR1C3 inhibitor in human tumor cell cultures and xenografts, suggesting its potential use to ameliorate PR-104 toxicity in patients. However, neither naproxen nor the pan-CYP inhibitor 1-aminobenzotriazole inhibited normal tissue reduction of PR-104A in mice.PR-104 is extensively reduced in mouse tissues, apparently via oxygen-independent two-electron reduction, with a tissue distribution that broadly reflects toxicity.