Nucleic Acids Research, Vol 24, Issue 2 336-341, Copyright © 1996 by Oxford University Press
V Brabec, O Vrana, O Novakova, V Kleinwachter, FP Intini, M Coluccia and G Natile
It has been shown recently that some analogues of clinically ineffective
trans-diamminedichloroplatinum (II) (transplatin) exhibit antitumor
activity. This finding has inverted the empirical structure- antitumor
activity relationships delineated for platinum(II) complexes, according to
which only the cis geometry of leaving ligands in the bifunctional platinum
complexes is therapeutically active. As a result, interactions of trans
platinum compounds with DNA, which is the main pharmacological target of
platinum anticancer drugs, are of great interest. The present paper
describes the DNA binding of antitumor trans-[PtCl(2)(E-imino ether)(2)]
complex (trans-EE) in a cell-free medium, which has been investigated using
three experimental approaches. They involve thiourea as a probe of
monofunctional DNA adducts of platinum (II) complexes with two leaving
ligands in the trans configuration, ethidium bromide as a probe for
distinguishing between monofunctional and bifunctional DNA adducts of
platinum complexes and HPLC analysis of the platinated DNA enzymatically
digested to nucleosides. The results show that bifunctional trans-EE
preferentially forms monofunctional adducts at guanine residues in
double-helical DNA even when DNA is incubated with the platinum complex for
a relatively long time (48 h at 37 degrees C in 10 mM NaCIO(4). It implies
that antitumor trans-EE modifies DNA in a different way than clinically
ineffective transplatin, which forms prevalent amount of bifunctional DNA
adducts after 48 h. This result has been interpreted to mean that the major
adduct of trans-EE, occurring in DNA even after long reaction times, is a
monofunctional adduct in which the reactivity of the second leaving group
is markedly reduced. It has been suggested that the different properties of
the adducts formed on DNA by transplatin and trans-EE are relevant to their
distinct clinical efficacy.
ARTICLES
DNA adducts of antitumor trans-[PtCl2 (E-imino ether)2]
Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
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