title: CpG methylation increases the DNA binding of 9-aminoacridine carboxamide Pt analogues.
abstract: This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-aminoacridine carboxamide Pt complexes are known to bind at 5'-CpG sequences. Their binding to methylated and non-methylated 5'-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5'-CpG was shown to significantly increase the binding intensity for the 9-aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5'-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell's genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use.
authors: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors: Hieronimus W
authors: HW
authors: Kava
authors: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: v.murray@unsw.edu.au.
authors: Vincent
authors: V
authors: Murray
mesh_terms: D000585:Aminacrine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002945:Cisplatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D018899:CpG Islands / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism
chemical_list: D007364:Intercalating Agents; D009944:Organoplatinum Compounds; D000585:Aminacrine; D004247:DNA; D002945:Cisplatin
keywords: 9-Aminoacridine; Anticancer drug; Cisplatin; Cisplatin analogues; DNA sequence specificity; Methylation; Polymerase stop assay