Dissociation of DNA from histone by reaction of anti-cancer drug cis-diamminedichloroplatinum(II) with DNA-histone complexes used as cellular model

Abstract

Although both cis-diamminedichloroplatinum(II) (cisplatin or cis-DDP) and trans-diamminedichloroplatinum(II) bind to DNA, only cis-DDP is widely used as a chemotherapeutic agent; the stereoisomer trans-DDP is inactive. DNA, generally, is wound around the histone core in the nucleus of living cells and forms the nucleosome structure. To understand the essentially different anticancer activities of cis-DDP and trans-DDP, it is necessary to investigate the interaction of cis-DDP (or trans-DDP) with DNA around the histone in the nucleosome. Here, we used φX174DNA-histoneLNCaP complexes prepared by the reaction of φX174DNA with histoneLNCaP extracted from LNCaP cells. We first show that the ability of cis-DDP to dissociate the DNA from φX174DNA-histoneLNCaP, as a nucleosome model, is much stronger than that of trans-DDP. As a result of the action of cis-DDP, the DNA in the nucleosome is rendered naked, and the naked DNA is vulnerable to cis-DDP (or other drugs). This study describes a new model showing that the difference in the activities of cis-DDP and trans-DDP is related to the difference in their abilities to dissociate the DNA from the nucleosome. © 2007 Pharmaceutical Society of Japan.