Hejmadi M V, McKeown S R, Friery O P, McIntyre I A, Patterson L H, Hirst D G
School of Biomedical Science, University of Ulster at Jordanstown, N. Ireland, UK.
Br J Cancer. 1996 Feb;73(4):499-505. doi: 10.1038/bjc.1996.87.
AQ4N (1,4-bis-([2-(dimethylamino-N- oxide)ethyl]amino)5,8-dihydroxyanthracene-9,10-dione) is a novel bioreductive agent that can be reduced to a stable, DNA-affinic compound, AQ4. The alkaline comet assay was used to evaluate DNA damage induced by AQ4N and radiation. Cells prepared from freshly excised T50/80 murine tumours were shown to have the ability to reduce AQ4N to a DNA-damaging agent; this had disappeared within 24 h of excision. When T50/80 tumours implanted in BDF mice were exposed to radiation in vivo a considerable amount of DNA damage was present in tumours excised immediately. Minimal levels of DNA damage were detectable in tumours excised after 2-5 h. AQ4N given 30 min before radiation had no appreciable influence on this effect and AQ4N alone caused only a small amount of damage. When AQ4N and radiation were combined an increasing number of damaged cells were seen in tumours excised 24-96 h after irradiation. This was interpreted as evidence of the continued presence of AQ4, or AQ4-induced damage, which was formed in cells hypoxic at the time of administration of AQ4N. AQ4, a potent topoisomerase II inhibitor, would be capable of damaging cells recruited into the cell cycle following radiation damage to the well-oxygenated cells of the tumour. The kinetics of the expression of the DNA damage is consistent with this hypothesis and shows that AQ4 has persistent activity in vivo.
AQ4N（1,4-双（[2-（二甲氨基-N-氧化物）乙基]氨基）-5,8-二羟基蒽醌-9,10-二酮）是一种新型的生物还原剂，可被还原为一种稳定的、与DNA有亲和力的化合物AQ4。碱性彗星试验用于评估AQ4N和辐射诱导的DNA损伤。结果显示，从新鲜切除的T50/80小鼠肿瘤制备的细胞具有将AQ4N还原为DNA损伤剂的能力；这种能力在切除后24小时内消失。当将植入BDF小鼠体内的T50/80肿瘤进行体内辐射时，立即切除的肿瘤中存在大量DNA损伤。在2-5小时后切除的肿瘤中可检测到最低水平的DNA损伤。在辐射前30分钟给予AQ4N对这种效应没有明显影响，单独使用AQ4N仅造成少量损伤。当AQ4N与辐射联合使用时，在照射后24-96小时切除的肿瘤中可见受损细胞数量增加。这被解释为在给予AQ4N时处于缺氧状态的细胞中持续存在AQ4或AQ4诱导损伤的证据。AQ4是一种有效的拓扑异构酶II抑制剂，能够损伤肿瘤中富氧细胞受到辐射损伤后进入细胞周期的细胞。DNA损伤表达的动力学与该假设一致，表明AQ4在体内具有持久活性。
