DNA Modifications by Antitumortrans-[PtCl2(E-Iminoether)2]
- Renata Žaludová1,
- Alena Žákovská1,
- Jana Kašpárkova1,
- Zdenka Balcarová1,
- Oldřich Vrána1,
- Mauro Coluccia2,
- Giovanni Natile3 and
- Viktor Brabec1
- 1Institute 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.),2Department of Biomedical Sciences and Human Oncology, Section of General Pathology and Experimental Oncology, Hospital, I-70124 Bari, Italy (M.C.), and 3Department of Pharmaceutical Chemistry, University of Bari, I-70125 Bari, Italy (G.N.)
Abstract
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 thecis geometry of leaving ligands in the bifunctional platinum(II) complexes, should be therapeutically active. Global modifications of natural DNAs in cell-free media bytrans-[PtCl2(E-iminoether)2] were studied through various molecular biophysical methods and compared with modifications bycis-[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 bytrans-[PtCl2(E-iminoether)2] is a monofunctional adduct at guanine residues. The modification bytrans-[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 oftrans-[PtCl2(E-iminoether)2] and transplatin has been suggested to be relevant to the unexpected observation that the new complex with leaving chloride groups intrans 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.
Footnotes
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Send reprint requests to: Dr. Viktor Brabec, Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, CZ-61265 Brno, Czech Republic.
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↵1 Promega. Protocols and Applications, 43–46 (1989/90).
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This work was supported by the Grant Agency of the Academy of Sciences of the Czech Republic (A5004702), Grant Agency of the Czech Republic (307/96/0996 and 301/95/1264), and Ministero dell’Universitá e della Ricerca Scientifica e Tecnologica of Italy. V.B. was supported in part by an International Research Scholarship from the Howard Hughes Medical Institute. This research is also a part of the European Cooperation in the field of Scientific and Technical Research Network (COST; project D1and D8).
- Abbreviations:
- cisplatin
- cis-diamminedichloroplatinum(II) (cis-[PtCl2(NH3)2])
- transplatin
- trans-diamminedichloroplatinum(II) (trans-[PtCl2(NH3)2])
- Me
- methyl
- cis-EE
- cis-[PtCl2(E-iminoether)2] (iminoether = HN⋕C(OMe)—Me
- it can have either E orZ configuration depending on the relative position of OMe and N-bonded Pt with respect to the C⋕N double bond
- cisin the Z isomer and trans in the Eisomer)
- trans-EE
- trans-[PtCl2(E-iminoether)2]
- dienPt
- chlorodiethylenetriamineplatinum(II) chloride {[PtCl(H2NCH2CH2NHCH2CH2NH2)]Cl}
- tm
- DNA melting temperature
- DPP
- differential pulse polarography
- ELISA
- enzyme-linked immunosorbent assay
- ICL
- interstrand cross-link or cross-linking
- bp
- base pair(s)
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- Received February 4, 1997.
- Accepted May 15, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
