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aludová,ákovská,
párkova,
ich
Vrána,
Institute of Biophysics, Academy of Sciences of the Czech Republic,
CZ-61265 Brno, Czech Republic (R.Z., A.Z., J.K., Z.B., O.V., V.B.),
Department of Biomedical Sciences and Human Oncology, Section of
General Pathology and Experimental Oncology, Hospital, I-70124 Bari,
Italy (M.C.), and
Department of Pharmaceutical Chemistry, University of
Bari, I-70125 Bari, Italy (G.N.)
Recent findings that an analogue of clinically ineffective transplatin,
trans-[PtCl2(E-iminoether)2],
exhibits antitumor activity has helped reevaluation of the empirical
structure-antitumor activity relationship generally accepted for
platinum(II) complexes. According to this relationship, only the
cis geometry of leaving ligands in the bifunctional
platinum(II) complexes, should be therapeutically active. Global
modifications of natural DNAs in cell-free media by
trans-[PtCl2(E-iminoether)2]
were studied through various molecular biophysical methods and compared
with modifications by
cis-[PtCl2(E-iminoether)2], transplatin, cisplatin, and monofunctional
chlorodiethylenetriamineplatinum(II) chloride. Thus, the results of
this study have extended our recent finding, indicating that the
prevalent lesion occurring in double-helical DNA on its modification by
trans-[PtCl2(E-iminoether)2]
is a monofunctional adduct at guanine residues. The modification by
trans-[PtCl2(E-iminoether)2] has been found to induce local distortions in DNA, which have a
character differing fundamentally from those induced by both clinically
ineffective or antitumor platinum complexes tested in this study. The
different character of alterations induced in DNA by the adducts of
trans-[PtCl2(E-iminoether)2]
and transplatin has been suggested to be relevant to the unexpected
observation that the new complex with leaving chloride groups in
trans position exhibits antitumor efficacy. In addition, the
results support the idea that platinum drugs that bind to DNA in a
manner fundamentally different from that of cisplatin can exhibit
altered biological properties, including differing spectra and
intensities of antitumor activity.
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