Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo.
Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo.
复制标题
米索硝唑在体内增强美法仑 DNA 交联活性。
DOI：
10.1038/bjc.1983.27
复制
发表时间：
1983
影响因子：
8.8
通讯作者：
Meyn,RE
中科院分区：
文献类型：
--
作者：
Murray,D;Meyn,RE
碱性洗脱技术已被用于体内药物诱导的DNA交联形成的研究。米索咪唑（MISO）的预处理增强了在纤维肉瘤中形成的交联的数量，并在小鼠的脾脏和肠道中，在单次注射美法仑（MEL）后长达48小时。肿瘤的致敏因子（2.05）大于正常组织（增强因子1.4-1.5）。这种增强似乎与抑制实际交联的修复无关。相反，这种影响可以用两种替代模型中的一种来解释。首先，MISO预处理可导致MEL在注射后早期与DNA结合的量更大。这可能是MEL的药代动力学改变或MISO预处理导致MEL的细胞内摄取增强的结果。其次，MISO可能通过在注射后早期抑制交联或单加合物的修复来发挥其作用，这在本研究中未观察到。通过与已知的巯基耗尽试剂马来酸二乙酯（DEM）的作用进行比较，研究了谷胱甘肽耗尽在MISO化学增敏中的可能参与。谷氨酰胺消耗虽然可能很重要，但不能解释观察到的所有影响。
The technique of alkaline elution has been adapted for the study of drug-induced DNA cross-link formation in vivo. Pretreatment with misonidazole (MISO) enhances the number of cross-links formed in a fibrosarcoma and in the spleen and gut of mice for periods up to 48 h following a single injection of melphalan (MEL). The tumour was sensitized by a greater factor (2.05) than either of the normal tissues (enhancement factor 1.4-1.5). This enhancement did not appear to be related to inhibition of the repair of actual cross-links. Rather, the effect was explicable in terms of one of two alternative models. Firstly, MISO pretreatment could result in a greater amount of binding of MEL to DNA at early times after injection. This may be the result of altered pharmacokinetics of MEL, or of enhanced intracellular uptake of MEL due to MISO pretreatment. Secondly, MISO may exert its affect by inhibition of the repair of cross-links or monoadducts at early times post-injection, which would not be observed in this study. The possible involvement of glutathione depletion in chemosensitization by MISO was investigated by comparison with the effect of diethyl maleate (DEM), a known thiol-depleting reagent. Glutathione depletion, while perhaps being important, could not account for all of the effects observed.