Zeman S M, Phillips D R, Crothers D M
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06511, USA.
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11561-5. doi: 10.1073/pnas.95.20.11561.
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.
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。
