Wilson W R, Siim B G, Denny W A, van Zijl P L, Taylor M L, Chambers D M, Roberts P B
Department of Pathology, University of Auckland School of Medicine, New Zealand.
Radiat Res. 1992 Sep;131(3):257-65.
Targeting of electron-affinic radiosensitizers to DNA via noncovalent binding (e.g., intercalation) may offer the potential for increasing sensitizing efficiency. However, it has been suggested that high-affinity DNA binding may compromise sensitization by restricting the mobility of sensitizers along the DNA, and by decreasing rates of extravascular diffusion in tumors. The weak DNA intercalator nitracrine (1-NC) is a more efficient radiosensitizer than related nitroacridines with higher DNA-binding affinities (Roberts et al., Radiat. Res. 123, 153-164, 1990). The present study investigates whether electron-affinic agents of even lower DNA-binding affinity may be superior to nitroacridines. The quinoline analog of 1-NC, 5-nitraquine (5-NO), was shown to have an intrinsic association constant for calf thymus DNA in 20 mM phosphate buffer which was 12-fold lower than that of 1-NC. 5-Nitraquine was not accumulated as efficiently as 1-NC by AA8 cells, but, despite a similar one-electron reduction potential, was 2- to 3-fold more potent than 1-NC as a hypoxia-selective radiosensitizer in vitro when compared on the basis of average intracellular concentration. Thus the radiosensitizing potency of 5-NQ appears not to be compromised by its low DNA-binding affinity. The cytotoxic mechanisms of 5-NQ and 1-NC appear to be similar (hypoxia-selective formation of DNA monoadducts), but 5-NQ is 1200-fold less potent than 1-NC as a cytotoxin. Despite this advantage, 5-NQ was not active in vivo as a radiosensitizer in SCCVII tumors. This lack of activity appears to be due to its relatively high toxicity in vivo (intraperitoneal LD50 of 105 mumol kg-1 in C3H/HeN mice), high one-electron reduction potential (-286 mV), and rapid metabolism to the corresponding amine in mice. The in vitro therapeutic index (hypoxic radiosensitizing potency/aerobic cytotoxic potency) of this weak DNA binder was lower than that of the non-DNA targeted radiosensitizer misonidazole, suggesting that DNA targeting enhances cytotoxicity more than radiosensitization. Development of useful DNA-targeted radiosensitizers may require the exploitation of DNA binding modes different from those of the nitroacridines and nitroquinolines.
通过非共价结合（如嵌入）将亲电子放射增敏剂靶向DNA可能为提高增敏效率提供潜力。然而，有人提出，高亲和力的DNA结合可能会通过限制增敏剂沿DNA的移动性以及降低肿瘤血管外扩散速率来损害增敏效果。弱DNA嵌入剂硝吖啶（1-NC）比具有更高DNA结合亲和力的相关硝基吖啶更有效地作为放射增敏剂（罗伯茨等人，《放射研究》123，153 - 164，1990）。本研究调查了DNA结合亲和力更低的亲电子剂是否可能优于硝基吖啶。1-NC的喹啉类似物5-硝基喹啉（5-NO）在20 mM磷酸盐缓冲液中对小牛胸腺DNA的固有缔合常数比1-NC低12倍。AA8细胞对5-硝基喹啉的积累效率不如1-NC，但尽管其一电子还原电位相似，在基于平均细胞内浓度进行比较时，作为体外缺氧选择性放射增敏剂，其效力比1-NC高2至3倍。因此，5-NQ的放射增敏效力似乎并未因其低DNA结合亲和力而受到损害。5-NQ和1-NC的细胞毒性机制似乎相似（缺氧选择性形成DNA单加合物），但作为细胞毒素，5-NQ的效力比1-NC低1200倍。尽管有这个优势，但5-NQ在体内对SCCVII肿瘤作为放射增敏剂没有活性。这种缺乏活性似乎是由于其在体内相对较高的毒性（C3H/HeN小鼠腹腔内LD50为105 μmol kg-1）、高的一电子还原电位（-286 mV）以及在小鼠体内快速代谢为相应的胺。这种弱DNA结合剂的体外治疗指数（缺氧放射增敏效力/需氧细胞毒性效力）低于非DNA靶向放射增敏剂米索硝唑，这表明DNA靶向增强细胞毒性的程度超过放射增敏。开发有用的DNA靶向放射增敏剂可能需要利用与硝基吖啶和硝基喹啉不同的DNA结合模式。
