Wilson W R, Anderson R F
Department of Pathology, University of Auckland School of Medicine, Private Bag, New Zealand.
Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):1001-5. doi: 10.1016/0360-3016(89)90903-6.
Nitracrine (NC) is an electron affinic DNA intercalating agent and a potent hypoxia-selective cytotoxin and radiosensitizer in cell culture. Although NC is too cytotoxic and too rapidly metabolized to provide hypoxic cell radiosensitization in tumors, it is of mechanistic interest as an example of a DNA affinic radiosensitizer. We have observed a rapid chemical reaction between NC and reduced glutathione (GSH), which suggests that the observed potent in vitro cytotoxicity and radiosensitization might be dependent on thiol depletion by the large extracellular reservoir of drug. However, no GSH depletion was observed under conditions providing radiosensitization or rapid cell killing, and prior depletion of GSH by buthionine sulphoximine had no effect on cytotoxicity or formation of macromolecular adducts. Further, the intracellular reaction of NC with GSH is slower than predicted on the basis of the measured second order rate constant and the total intracellular concentrations of both species. The results are consistent with a role for DNA binding in protecting NC from reaction with GSH, and in improving the efficiency with which reduced electrophilic metabolites react with DNA in preference to GSH.
硝吖啶（NC）是一种亲电子性的DNA嵌入剂，在细胞培养中是一种强效的缺氧选择性细胞毒素和放射增敏剂。尽管NC的细胞毒性太强且代谢太快，无法在肿瘤中实现缺氧细胞放射增敏作用，但作为一种DNA亲和性放射增敏剂的例子，它在机制方面具有研究价值。我们观察到NC与还原型谷胱甘肽（GSH）之间发生了快速化学反应，这表明所观察到的强大体外细胞毒性和放射增敏作用可能依赖于药物在细胞外大量蓄积导致的巯基耗竭。然而，在提供放射增敏或快速细胞杀伤的条件下未观察到GSH耗竭，并且用丁硫氨酸亚砜胺预先耗尽GSH对细胞毒性或大分子加合物的形成没有影响。此外，NC与GSH在细胞内的反应比根据测得的二级速率常数和两种物质的细胞内总浓度所预测的要慢。这些结果与DNA结合在保护NC不与GSH反应以及提高还原型亲电子代谢物优先与DNA而非GSH反应的效率方面所起的作用一致。
