DNA Interactions of a Novel Platinum Drug, cis-[PtCl(NH3)2(N7-Acyclovir)]+
- Zdenka Balcarová1,
- Jana Kaspárková1,
- Alena Zákovská1,
- Olga Nováková1,
- Maria F. Sivo2,
- Giovanni Natile3 and
- Viktor Brabec1
- 1Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic (Z.B., J.K., A.Z., O.N., V.B.),2Cancer Research Center, c/o Department of Biochemistry and Molecular Biology, University of Bari, I-70125 Bari, Italy (M.S.S.), and3Department of Pharmaceutical Chemistry, University of Bari, I-70125 Bari, Italy (G.N.)
Abstract
We synthesized a novel platinum drug,cis-[PtCl(NH3)2(N7-ACV)]+, in which ACV is the antiviral drug acyclovir [a deoxyriboguanosine analogue, 9-(2-hydroxyethoxymethyl)guanine]. This new compound exhibits antiviral efficacy in vitro and exhibits an antitumor activity profile different from that of cisplatin [Metal-Based Drugs 2:249–256 (1995)]. To contribute to understanding the mechanisms underlying biological activity of this new compound, we studied modifications of natural and synthetic DNAs in cell-free media bycis-[PtCl(NH3)2(N7-ACV)]+by various biochemical and biophysical methods. The results indicated that the major DNA adduct ofcis-[PtCl(NH3)2(N7-ACV)]+was a stable monofunctional adduct at guanine residues. In contrast to DNA adducts of other monodentate and clinically ineffective platinum(II) compounds, the adducts ofcis-[PtCl(NH3)2(N7-ACV)]+terminated in vitro DNA and RNA synthesis. In addition, although DNA adducts ofcis-[PtCl(NH3)2(N7-ACV)]+and cisplatin were different, some properties of DNA modified by either compound were qualitatively similar. Such similarities were not noticed if DNA modifications by other ineffective monofunctional platinum(II) complexes were investigated. Thus, the DNA binding mode of monofunctionalcis-[PtCl(NH3)2(N7-ACV)]+was different from that of other monofunctional but ineffective platinum(II) complexes. It has been suggested that the unique capability ofcis-[PtCl(NH3)2(N7-ACV)]+to modify DNA may be relevant to a distinct antitumor efficiency of this novel drug in comparison with cisplatin. It also has been suggested that at least some aspects of DNA interactions ofcis-[PtCl(NH3)2(ACV)]+revealed in the current study could be exploited in the search for and development of new antiviral platinum complexes containing, as a part of the coordination sphere, antiviral nucleosides.
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. E-mail:brabec{at}ibp.cz
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This work was supported by the Grant Agency of the Czech Republic (Grants 301/95/1264 and 307/96/0996), the Grant Agency of the Academy of Sciences of the Czech Republic (Grant A5004702), and the Ministero dell’Universita’ e della Ricerca Scientifica e Tecnologica of Italy. The research of Viktor Brabec was supported in part by an International Research Scholar′s award from the Howard Hughes Medical Institute. This research also is a part of the European Cooperation in the field of Scientific and Technical Research Network (COST; Projects D8/0009/97 and D8/0012/97).
- Abbreviations:
- ACV
- acyclovir
- cisPt-ACV
- cis-[PtCl(NH3)2(N7-ACV)]+complex
- dienPt
- chlorodiethylenetriamineplatinum(II) chloride
- DMS
- dimethylsulfate
- ELISA
- enzyme-linked immunosorbent assay
- FAAS
- flameless atomic absorption spectrophotometry
- RP-HPLC
- reversed-phase high performance liquid chromatography
- ICL
- interstrand cross-link
- ri
- molar ratio of free platinum complex to nucleotide phosphates at the onset of incubation with DNA
- rb
- number of the molecules of platinum complex fixed per nucleotide residue
- tm
- DNA melting temperature
- transplatin
- trans-diamminedichloroplatinum(II)
- transPt-ACV
- trans-[PtCl(NH3)2(N7-ACV)]+complex
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- Received October 14, 1997.
- Accepted January 27, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
