共价阿霉素 - DNA加合物的表征
Characterization of covalent adriamycin-DNA adducts.
作者信息
Zeman S M, Phillips D R, Crothers D M
机构信息
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06511, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11561-5. doi: 10.1073/pnas.95.20.11561.
Abstract
Adriamycin is a popular antineoplastic agent whose ability to form covalent adducts with DNA has been correlated to cellular apoptosis (programmed cell death) in tumor models. We have isolated and purified this adduct formed under oxido-reductive (Fenton) conditions in Tris buffer. We show by homo- and heteronuclear NMR spectroscopy that the covalent Adriamycin-DNA adduct is structurally equivalent to that resulting from direct reaction with formaldehyde. Covalent linkage of the drug to one of the DNA strands confers remarkable stability to the duplex, indicated by a 162-fold reduction in the rate of strand displacement compared with the complex with noncovalently bound drug. Glyceraldehyde also engenders covalent Adriamycin-DNA complexes, providing a possible relevant biological context for in vivo adduct formation.
摘要
阿霉素是一种常用的抗肿瘤药物，在肿瘤模型中，其与DNA形成共价加合物的能力与细胞凋亡（程序性细胞死亡）相关。我们已经在Tris缓冲液中，通过氧化还原（芬顿）条件分离并纯化了这种加合物。我们通过同核和异核核磁共振光谱表明，共价阿霉素-DNA加合物在结构上等同于与甲醛直接反应产生的加合物。药物与其中一条DNA链的共价连接赋予双链显著的稳定性，与非共价结合药物的复合物相比，链置换速率降低了162倍。甘油醛也能产生共价阿霉素-DNA复合物，为体内加合物的形成提供了可能相关的生物学背景。
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本文引用的文献
1
Production of formaldehyde and DNA-adriamycin or DNA-daunomycin adducts, initiated through redox chemistry of dithiothreitol/iron, xanthine oxidase/NADH/iron, or glutathione/iron.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以及DNA-阿霉素或DNA-柔红霉素加合物的生成。
Chem Res Toxicol. 1997 Sep;10(9):953-61. doi: 10.1021/tx970064w.
2
Redox pathway leading to the alkylation of DNA by the anthracycline, antitumor drugs adriamycin and daunomycin.导致蒽环类抗肿瘤药物阿霉素和柔红霉素使DNA烷基化的氧化还原途径。
J Med Chem. 1997 Apr 11;40(8):1276-86. doi: 10.1021/jm960835d.
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Alkylation of DNA by the anthracycline, antitumor drugs adriamycin and daunomycin.蒽环类抗肿瘤药物阿霉素和柔红霉素对DNA的烷基化作用。
J Med Chem. 1996 Oct 11;39(21):4135-8. doi: 10.1021/jm960519z.
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Simultaneous incorporations of two anticancer drugs into DNA. The structures of formaldehyde-cross-linked adducts of daunorubicin-d(CG(araC)GCG) and doxorubicin-d(CA(araC)GTG) complexes at high resolution.两种抗癌药物同时掺入DNA。柔红霉素-d（CG（阿糖胞苷）GCG）和阿霉素-d（CA（阿糖胞苷）GTG）复合物经甲醛交联后的加合物在高分辨率下的结构。
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Does adriamycin induce interstrand cross-links in DNA?阿霉素会诱导DNA链间交联吗？
Biochemistry. 1994 Apr 19;33(15):4632-8. doi: 10.1021/bi00181a025.
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Relevance of interstrand DNA crosslinking induced by anthracyclines for their biological activity.蒽环类药物诱导的链间DNA交联与其生物学活性的相关性。
Biochem Pharmacol. 1994 Jun 15;47(12):2279-87. doi: 10.1016/0006-2952(94)90266-6.
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Interstrand DNA crosslinking induced by anthracyclines in tumour cells.蒽环类药物在肿瘤细胞中诱导的链间DNA交联。
Biochem Pharmacol. 1994 Jun 15;47(12):2269-78. doi: 10.1016/0006-2952(94)90265-8.
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Use of oligonucleotides to define the site of interstrand cross-links induced by Adriamycin.使用寡核苷酸确定阿霉素诱导的链间交联位点。
Nucleic Acids Res. 1995 Jul 11;23(13):2450-6. doi: 10.1093/nar/23.13.2450.
10
Enzymatic activation and binding of adriamycin to nuclear DNA.阿霉素与核DNA的酶促活化及结合
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