Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry
Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry
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DOI：
10.1002/rcm.2952
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发表时间：
2007-01-01
影响因子：
2
通讯作者：
Clench, Malcolm R.
中科院分区：
文献类型：
--
作者：
Atkinson, Sally J.;Loadman, Paul M.;Clench, Malcolm R.
AQ 4 N（banoxatrone）（1，4-双-{[2-（二甲基氨基-N-氧化物）乙基]氨基}-5，8-二羟基蒽-9，10-二酮）是临床开发中的生物还原性前药的实例。在缺氧细胞中，AQ 4 N被还原为拓扑异构酶II抑制剂AQ 4（1，4-双-{[2-（二甲氨基）乙基]氨基}1- 5，8-二羟基蒽-9，10-二酮）。通过抑制这些缺氧区域内的拓扑异构酶11，AQ 4 N已被证明可使肿瘤对现有的化疗和放疗治疗敏感。在这项研究中，AQ 4 N和AQ 4在治疗的H460人肿瘤异种移植物中的分布已经通过成像基质辅助激光解吸/电离质谱法进行了检查。AQ 4 N和AQ 4的分布图像已经产生，显示很少重叠。还研究了肿瘤异种移植物中ATP的分布，作为缺氧区域的内源性标志物，因为已知ATP浓度在这些区域中降低。ATP的分布与AQ 4 N相似，即在富含ATP的区域，没有证据表明AQ 4 N转化为AQ 4。这表明细胞毒性代谢物AQ 4如预期的那样局限于肿瘤的缺氧区域。版权所有（c）2007约翰威利父子有限公司。
AQ4N (banoxatrone) (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9, 10-dione) is an example of a bioreductive prodrug in clinical development. In hypoxic cells AQ4N is reduced to the topoisomerase II inhibitor AQ4 (1,4-bis-{[2-(dimethylamino)ethyl] amino}1-5,8-dilhydroxyanthracene-9,10-dione). By inhibition of topoisomerase 11 within these hypoxic areas, AQ4N has been shown to sensitise tumours to existing chemo- and radiotherapy treatments. In this study the distribution of AQ4N and AQ4 in treated H460 human tumour xenografts has been examined by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Images of the distribution of AQ4N and AQ4 have been produced that show little overlap. The distribution of ATP in the tumour xenografts was also studied as an endogenous marker of regions of hypoxia since concentrations of ATP are known to be decreased in these regions. The distribution of ATP was similar to that of AQ4N, i.e. in regions of abundant ATP there was no evidence of conversion of AQ4N into AQ4. This indicates that the cytotoxic metabolite AQ4 is confined to hypoxic regions of the tumour as intended. Copyright (c) 2007 John Wiley & Sons, Ltd.