Interaction of antitumor drug, mithramycin, with chromatin

Mithramycin (MTR) is an anticancer drug that blocks macromolecular biosynth esis via reversible interaction with DNA in the presence of bivalent cation such as Mg2+. Mithramycin forms two types of complexes with Mg2+: complex I (1:1 in terms of MTR:Mg2+) and complex II (2:1 in terms of MTR:Mg2+). In vivo antibiotic would interact with chromatin, a protein-DNA complex. For t he first time we have demonstrated and characterized the association of bot h complexes of MTR with chromatin and nucleosome core. From an evaluation a nd comparison of the binding and thermodynamic parameters and CD spectra of bound complexes, we have shown the following. Histone(s) stand in the say of the access of the ligand(s) to chromosomal DNA. Chromatin and core parti cle interact differentially with the same ligand. Mode of interaction of th e two complexes, I and II, with the same system is different. Significance of these results to understand the transcription inhibitory property of the drug in eukaryotic chromosome is discussed, (C) 2001 Academic Press.