DNA Interactions of New Antitumor Aminophosphine Platinum(II) Complexes
- Kamila Neplechová1,
- Jana Kašpárková1,
- Oldřich Vrána1,
- Olga Nováková1,
- Abraha Habtemariam2,
- Beth Watchman2,
- Peter J. Sadler2 and
- Viktor Brabec1
- 1Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic (K.N., J.K., O.V., O.N., V.B.); and 2Department of Chemistry, University of Edinburgh, Edinburgh, United Kingdom (A.H., B.W., P.J.S.)
Abstract
Mechanistic studies are presented of a novel class of aminophosphine platinum(II) complexes as potential anticancer agents. These new agents, which have demonstrated activity against murine and human tumor cells including those resistant to cisplatin arecis-[PtCl2(Me2N(CH2)3PPh2-P)2] (Com1) and cis-[PtCl(C6H11NH(CH2)2PPh2-N,P)(C6H11NH(CH2)2PPh2-P)] (Com2). We studied modifications of natural and synthetic DNAs in cell-free media by Com1 and Com2 by various biomedical and biophysical methods and compared the results with those obtained when DNA was modified by cisplatin. The results indicated that Com1 and Com2 coordinated to DNA faster than cisplatin. Bifunctional Com1 formed DNA adducts coordinating to single adenine or guanine residues or by forming cross-links between these residues. In comparison with cisplatin, Com1 formed the adducts more frequently at adenine residues and also formed fewer bidentate lesions. The monofunctional Com2 only formed DNA monodentate adducts at guanine residues. In addition, Com1 terminated DNA synthesis in vitro more efficiently than cisplatin whereas Com2 blocked DNA synthesis only slightly. DNA unwinding studies, measurements of circular dichroism spectra, immunochemical analysis, and studies of the B-Z transition in DNA revealed conformational alterations induced by the adducts of Com1, which were distinctly different from those induced by cisplatin. Com2 had little influence on DNA conformation. It is suggested that the activity profile of aminophosphine platinum(II) complexes, which is different from that of cisplatin and related analogs, might be associated with the specific DNA binding properties of this new class of platinum(II) compounds.
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 Grants 305/99/0695, 301/98/P231, 307/97/P029, and 204/97/P028 from the Grant Agency of the Czech Republic, Grants A5004702 and A7004805 from the Grant Agency of the Academy of Sciences of the Czech Republic, the Biotechnology and Biological Sciences Research Council, and the Engineering and Physical Sciences Research Council. V.B. is the recipient of an International Research Scholar’s award from the Howard Hughes Medical Institute. This research is part of the European Cooperation in the Field of Scientific and Technical Research program (Projects D8/0009/97 and D8/0012/97).
- Abbreviations:
- Com1
- cis-[PtCl2(Me2N(CH2)3PPh2-P)2]
- Com2
- cis-[PtCl(C6H11NH(CH2)2PPh2-N,P)(C6H11NH(CH2)2PPh2-P)]
- Abcis
- polyclonal antibodies that bind selectively to adducts formed on linear double-helical DNA by cisplatin at rb = 0.08
- bp
- base pair(s)
- CD
- circular dichroism
- cisplatin
- cis-diamminedichloroplatinum(II) {cis-[PtCl2(NH3)2]}
- [PtCl(dien)]Cl
- chlorodiethylenetriamineplatinum(II) chloride {[PtCl(H2NCH2CH2NHCH2CH2NH2)]Cl}
- DPP
- differential pulse polarography
- EtBr
- ethidium bromide
- FAAS
- flameless atomic absorption spectrophotometry
- RP
- reversed phase
- ICL
- interstrand cross-link
- rb, the number of the molecules of the platinum complex fixed per nucleotide residue
- ri, the molar ratio of free platinum complex to nucleotide-phosphates at the onset of incubation with DNA
- CT
- calf thymus
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- Received November 23, 1998.
- Accepted April 5, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
