The polyamines spermidine and spermine retard the platination rate of single-stranded DNA oligomers and plasmids.
The presence of polyamines in living cells is crucial for survival. Due to their high net charge at physiological pH, polyamines effectively charge neutralize the phosphodiester backbone of DNA in an interaction that also may protect the DNA from external damage. We here present a study illustrating the influence of spermidine and spermine on the platination reactions of the model oligonucleotides d(T(6)GT(6)), d(T(12)GT(12)), and d(T(24)GT(24)), and the pUC18 DNA plasmid. The aquated forms of the anticancer active compounds cisplatin (cis-[Pt(NH(3))(2)Cl(2)]) and the major Pt(II) metabolite of JM216 (cis-[PtCl(2)(NH(3))(c-C(6)H(11)NH(2))], JM118) were used as platination reagents. The study shows that the kinetics for formation of the coordinative Pt-DNA adduct are strongly influenced by the presence of sub-millimolar polyamine concentrations. At polyamine concentrations in the muM-range, the reactions remain salt-dependent. In contrast, platination of pUC18 is effectively prevented at mM concentrations of both spermidine and spermine with the latter as the more potent inhibitor. The results suggest that variations of intracellular polyamine concentrations may have a profound influence on the efficacy by which cationically charged reagents interfere with DNA function in vivo by modulation of the preassociation conditions.
Snygg
Ase Sykfont
AS
Department of Biochemistry, Chemical Center, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden.
Hung
Meiling
M
Elmroth
Sofi K C
SK
D002414:Cations, Monovalent; D018736:DNA Adducts / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D009841:Oligonucleotides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010957:Plasmids / Q000037:antagonists & inhibitors / Q000378:metabolism; D017671:Platinum Compounds / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012964:Sodium / Q000737:chemistry / Q000378:metabolism; D013095:Spermidine / Q000494:pharmacology*; D013096:Spermine / Q000494:pharmacology*
D002414:Cations, Monovalent; D018736:DNA Adducts; D004277:DNA, Single-Stranded; D009841:Oligonucleotides; D017671:Platinum Compounds; D013096:Spermine; D012964:Sodium; D013095:Spermidine