Murray D, Meyn R E
Br J Cancer. 1984 Dec;50(6):801-8. doi: 10.1038/bjc.1984.259.
In the present study we have used the alkaline elution technique to study the effect of misonidazole (MISO) on the initial amount of DNA cross-linking in various normal and neoplastic tissues of C3H mice treated with nitrogen mustard (HN2) in vivo. Tissue samples for analysis of the cross-links were prepared 1 h after injection with HN2 to minimize the effect of subsequent repair processes on the yield of lesions. For mice receiving HN2 alone, the greatest level of cross-linking was found in spleen and jejunum, with the liver showing the lowest level. In animals that had been pretreated with MISO (1 mg g-1, i.p.) for 0.5 h prior to injection with HN2, the amount of cross-linking in the spleen and jejunum was not affected by MISO; however, in all other tissues that were examined, cross-linking was enhanced by MISO to a varying extent depending on the specific tissue. The greatest enhancement was observed in the liver (X 6) and kidney (X 3.1), both of these tissues showing a greater enhancement than either of the two fibrosarcomas. The potentiation of HN2 cross-linking in a particular tissue correlated well with two cellular processes that are known to be nitroreduction-dependent in vitro, namely, the degree of MISO-induced GSH depletion and the binding of MISO to cellular macromolecules. Thus, the potentiation of cross-linking in normal tissues such as liver and kidney, and by inference in tumours, may be intimately related to the generation and/or accumulation of nitro-reduced MISO metabolites in those tissues.
在本研究中，我们使用碱性洗脱技术来研究米索硝唑（MISO）对体内用氮芥（HN2）处理的C3H小鼠各种正常组织和肿瘤组织中DNA交联初始量的影响。在注射HN2后1小时制备用于分析交联的组织样本，以尽量减少后续修复过程对损伤产量的影响。对于仅接受HN2的小鼠，脾脏和空肠中发现的交联水平最高，肝脏中的水平最低。在用HN2注射前0.5小时用MISO（1mg/g，腹腔注射）预处理的动物中，脾脏和空肠中的交联量不受MISO影响；然而，在所有其他检查的组织中，交联根据特定组织的不同程度被MISO增强。在肝脏（X6）和肾脏（X3.1）中观察到最大的增强，这两个组织的增强程度均高于两种纤维肉瘤中的任何一种。HN2在特定组织中的交联增强与体外已知的两种依赖硝基还原的细胞过程密切相关，即MISO诱导的谷胱甘肽耗竭程度和MISO与细胞大分子的结合。因此，肝脏和肾脏等正常组织以及由此推断肿瘤中的交联增强可能与这些组织中硝基还原的MISO代谢产物的产生和/或积累密切相关。
