Production of formaldehyde and DNA-adriamycin or DNA-daunomycin adducts, initiated through redox chemistry of dithiothreitol/iron, xanthine oxidase/NADH/iron, or glutathione/iron.
Production of formaldehyde and DNA-adriamycin or DNA-daunomycin adducts, initiated through redox chemistry of dithiothreitol/iron, xanthine oxidase/NADH/iron, or glutathione/iron.
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通过二硫苏糖醇/铁、黄嘌呤氧化酶/NADH/铁或谷胱甘肽/铁的氧化还原化学引发甲醛和DNA-阿霉素或DNA-道诺霉素加合物的生产。
DOI：
10.1021/tx970064w
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Koch,TH
中科院分区：
文献类型：
--
作者：
Taatjes,DJ;Gaudiano,G;Koch,TH
研究了抗肿瘤药物阿霉素和道诺霉素与自互补DNA寡核苷酸（GC）4生成DNA-药物加合物的反应，作为氧化还原反应条件的函数。氧化还原系统二硫苏糖醇（DTT）/Fe（III）和黄嘌呤氧化酶/NADH都给出了四种DNA-蒽环类加合物的相同分布。在这些加合物的每一种中，蒽环类药物通过药物的3 '-氨基和DNA的脱氧鸟苷的2-氨基之间的亚甲基连接键键合。亚甲基键是由药物和DNA在原位生成的甲醛内通过席夫碱化学反应产生的[Taatjes，D. J.，Gaudiano，G.，Resing，K.，Koch，T. H.（1997）J.Med.Chem.40，1276 - 1286]。甲醛的产生由铁促进，由金属螯合剂抑制，并且不需要药物。铁可使甲醛生成增加30倍，EDTA可抑制其形成2倍，Desferal可抑制其形成20倍以上。在去铁醛存在下，过氧化氢仅与黄嘌呤氧化酶/NADH大量蓄积。用芬顿氧化Tris缓冲液生成甲醛的方法对实验结果进行了解释。生物试剂也会导致DNA-药物加合物的形成;在精胺存在下，在磷酸盐缓冲液中用谷胱甘肽还原铁离子也会产生相同的DNA-药物加合物。观察结果进行了讨论，从铁螯合阿霉素catalyzingin体内生产的甲醛，连接阿霉素的DNA和肿瘤细胞的耐药性，减少甲醛的因素所产生的细胞毒性。
The reaction of the antitumor drugs adriamycin and daunomycin with the self-complementary DNA oligonucleotide (GC)4to generate DNA−drug adducts was investigated as a function of redox reaction conditions. The redox systems dithiothreitol (DTT)/Fe(III) and xanthine oxidase/NADH both gave the same distribution of four DNA−anthracycline adducts. In each of these adducts the anthracycline is bonded via a methylene linkage between the 3‘-amino group of the drug and the 2-amino group of a deoxyguanosine of the DNA. The methylene linkage results from reaction of the drug and DNA within situ-generated formaldehyde via Schiff base chemistry [Taatjes, D. J., Gaudiano, G., Resing, K., and Koch, T. H. (1997)J. Med. Chem.40, 1276−1286]. Formaldehyde production is promoted by iron, inhibited by metal-chelating agents, and does not require drug. Iron enhances formaldehyde production by a factor of 30, EDTA inhibits its formation by a factor of 2, and Desferal inhibits its formation by a factor of more than 20. Hydrogen peroxide accumulates in significant quantities only with xanthine oxidase/NADH in the presence of Desferal. The results are explained in terms of Fenton oxidation of Tris buffer to formaldehyde. Biological reagents also cause DNA−drug adduct formation; reduction of ferric ion with glutathione in phosphate buffer in the presence of spermine produced the same DNA−drug adducts. The observations are discussed in terms of cytotoxicity resulting from iron chelated to adriamycin catalyzingin vivoproduction of formaldehyde which links adriamycin to DNA and tumor cell resistance resulting from factors which decrease formaldehyde.