The structure-pharmacological activity relationships generally accepted for antitumor platinum compounds stressed the necessity for the cis-[PtX(2)(amine)(2)] structure while the trans-[PtX(2)(amine)(2)] structure was considered inactive. However, more recently, several trans-platinum complexes have been identified which are potently toxic, antitumor-active and demonstrate activity distinct from that of conventional cisplatin (cis-[PtCl(2)(NH(3))(2)]). We have shown in the previous report that the replacement of ammine ligands by iminoether in transplatin (trans-[PtCl(2)(NH(3))(2)]) results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant antitumor activity, including activity in cisplatin-resistant tumor cells. In addition, we have also shown previously that this new trans compound (trans-[PtCl(2)(E-iminoether)(2)]) forms mainly monofunctional adducts at guanine residues on DNA, which is generally accepted to be the cellular target of platinum drugs. In order to shed light on the mechanism underlying the antitumor activity of trans-[PtCl(2)(E-iminoether)(2)] we examined oligodeoxyribonucleotide duplexes containing a single, site-specific, monofunctional adduct of this transplatin analog by the methods of molecular biophysics. The results indicate that major monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] locally distort DNA, bend the DNA axis by 21 degrees toward the minor groove, are not recognized by HMGB1 proteins and are readily removed from DNA by nucleotide excision repair (NER). In addition, the monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA polymerases in vitro and to inhibit removal of this adduct from DNA by NER. It is suggested that DNA-protein ternary cross-links produced by trans-[PtCl(2)(E-iminoether)(2)] could persist considerably longer than the non-cross-linked monofunctional adducts, which would potentiate toxicity of this antitumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl(2)(E-iminoether)(2)] represents a quite new class of platinum antitumor drugs in which activation of trans geometry is associated with an increased efficiency to form DNA-protein ternary cross-links thereby acting by a different mechanism from 'classical' cisplatin and its analogs.

Institute of Biophysics Academy of Sciences of the Czech Republic CZ 61265 Brno

See more in PubMed

O'Dwyer P.J., Stevenson,J.P. and Johnson,S.W. (1999) Clinical status of cisplatin, carboplatin and other platinum-based antitumor drugs. In Lippert,B. (ed.), Cisplatin. Chemistry and Biochemistry of a Leading Anticancer Drug. VHCA, WILEY-VCH, Zürich, Weinheim, pp. 31–72.

Farrell N., Kelland,L.R., Roberts,J.D. and Van Beusichem,M. (1992) Activation of the trans geometry in platinum antitumor complexes: a survey of the cytotoxicity of trans complexes containing planar ligands in murine-L1210 and human tumor panels and studies on their mechanism of action. Cancer Res., 52, 5065–5072. PubMed

Wong E. and Giandomenico,C.M. (1999) Current status of platinum-based antitumor drugs. Chem. Rev., 99, 2451–2466. PubMed

Judson I. and Kelland,L.R. (2000) New developments and approaches in the platinum arena. Drugs, 59, 29–36. PubMed

Brabec V. (2002) DNA modifications by antitumor platinum and ruthenium compounds: their recognition and repair. Prog. Nucleic Acids Res. Mol. Biol., 71, 1–68. PubMed

Reedijk J. (1996) Improved understanding in platinum antitumour chemistry. Chem. Comm., 801–806.

Farrell N. (1996) Current status of structure-activity relationships of platinum anticancer drugs: Activation of the trans geometry. In Sigel,A. and Sigel,H. (eds), Metal Ions in Biological Systems. Marcel Dekker, Inc., New York, Basel, Hong Kong, Vol. 32, pp. 603–639. PubMed

Perez J.-M., Fuertes,M.A., Alonso,C. and Navarro-Ranninger,C. (2000) Current status of the development of trans-platinum antitumor drugs. Crit. Rev. Oncol. Hematol., 35, 109–120. PubMed

Natile G. and Coluccia,M. (1999) trans-Platinum compounds in cancer therapy: a largely unexplored strategy for identifying novel antitumor platinum drugs. In Clarke,M.J. and Sadler,P.J. (eds), Metallopharmaceuticals. Springer, Berlin, Germany, Vol. 1, pp. 73–98.

Coluccia M., Nassii,F., Loseto,F., Boccarelli,A., Marigió,M.A., Giordano,D., Intini,F.P., Caputo,P. and Natile,G. (1993) A trans-platinum complex showing higher antitumor activity than the cis congeners. J. Med. Chem., 36, 510–512. PubMed

Coluccia M., Boccarelli,A., Mariggio,M.A., Cardellicchio,N., Caputo,P., Intini,F.P. and Natile,G. (1995) Platinum(II) complexes containing iminoethers: A trans platinum antitumour agent. Chem. Biol. Interact., 98, 251–266. PubMed

Coluccia M., Nassi,A., Boccarelli,A., Giordano,D., Cardellicchio,N., Intini,F.P., Natile,G., Barletta,A. and Paradiso,A. (1999) In vitro antitumour activity and cellular pharmacological properties of the platinum-iminoether complex trans-[PtCl2{E-HN=C(OMe)Me}2]. Int. J. Oncol., 15, 1039–1044. PubMed

Brabec V., Vrana,O., Novakova,O., Kleinwachter,V., Intini,F.P., Coluccia,M. and Natile,G. (1996) DNA adducts of antitumor trans-[PtCl2(E-imino ether)2]. Nucleic Acids Res., 24, 336–341. PubMed PMC

Zaludova R., Zakovska,A., Kasparkova,J., Balcarova,Z., Vrana,O., Coluccia,M., Natile,G. and Brabec,V. (1997) DNA modifications by antitumor trans-[PtCl2(E-iminoether)2]. Mol. Pharmacol., 52, 354–361. PubMed

Brabec V., Kleinwächter,V., Butour,J.L. and Johnson,N.P. (1990) Biophysical studies of the modification of DNA by antitumour platinum coordination complexes. Biophys. Chem., 35, 129–141. PubMed

Lemaire M.A., Schwartz,A., Rahmouni,A.R. and Leng,M. (1991) Interstrand cross-links are preferentially formed at the d(GC) sites in the reaction between cis-diamminedichloroplatinum(II) and DNA. Proc. Natl Acad. Sci. USA, 88, 1982–1985. PubMed PMC

Brabec V. and Leng,M. (1993) DNA interstrand cross-links of trans-diamminedichloroplatinum(II) are preferentially formed between guanine and complementary cytosine residues. Proc. Natl Acad. Sci. USA, 90, 5345–5349. PubMed PMC

Andersen B., Margiotta,N., Coluccia,M., Natile,G. and Sletten,E. (2000) Antitumor trans platinum DNA adducts: NMR and HPLC study of the interaction between a trans-Pt iminoether complex and the deoxy decamer d(CCTCGCTCTC).d(GAGAGCGAGG). Metal-Based Drugs, 7, 23–32. PubMed PMC

Cini R., Caputo,P.A., Initini,F.P. and Natile,G. (1995) Mechanistic and stereochemical investigation of iminoethers formed by alcoholysis of coordinated nitrils: X-ray crystal structure of cis- and trans-[bis(1-imino-1-methoxyethane) dichloroplatinum(II)]. Inorg. Chem., 34, 1130–1137.

Brabec V., Reedijk,J. and Leng,M. (1992) Sequence-dependent distortions induced in DNA by monofunctional platinum(II) binding. Biochemistry, 31, 12397–12402. PubMed

Stros M. (1998) DNA bending by the chromosomal protein HMG1 and its high mobility group box domains. Effect of flanking sequences. J. Biol. Chem., 273, 10355–10361. PubMed

Stros M. (2001) Two mutations of basic residues within the N-terminus of HMG-1 B domain with different effects on DNA supercoiling and binding to bent DNA. Biochemistry, 40, 4769–4779. PubMed

Kasparkova J., Mellish,K.J., Qu,Y., Brabec,V. and Farrell,N. (1996) Site-specific d(GpG) intrastrand cross-links formed by dinuclear platinum complexes. Bending and NMR studies. Biochemistry, 35, 16705–16713. PubMed

Brabec V., Sip,M. and Leng,M. (1993) DNA conformational distortion produced by site-specific interstrand cross-link of trans-diamminedichloroplatinum(II). Biochemistry, 32, 11676–11681. PubMed

Koo H.S., Wu,H.M. and Crothers,D.M. (1986) DNA bending at adenine·thymine tracts. Nature, 320, 501–506. PubMed

Bellon S.F. and Lippard,S.J. (1990) Bending studies of DNA site-specifically modified by cisplatin, trans-diamminedichloroplatinum(II) and cis-Pt(NH3)2(N3-cytosine)Cl+. Biophys. Chem., 35, 179–188. PubMed

Kasparkova J., Farrell,N. and Brabec,V. (2000) Sequence specificity, conformation and recognition by HMG1 protein of major DNA interstrand cross-links of antitumor dinuclear platinum complexes. J. Biol. Chem., 275, 15789–15798. PubMed

Bailly C., Gentle,D., Hamy,F., Purcell,M. and Waring,M.J. (1994) Localized chemical reactivity in DNA associated with the sequence-specific bisintercalation of echinomycin. Biochem. J., 300, 165–173. PubMed PMC

Ross S.A. and Burrows,C.J. (1996) Cytosine-specific chemical probing of DNA using bromide and monoperoxysulfate. Nucleic Acids Res., 24, 5062–5063. PubMed PMC

Bailly C. and Waring,M.J. (1997) Diethylpyrocarbonate and osmium tetroxide as probes for drug-induced changes in DNA conformation in vitro. In Fox,K.R. (ed.), Drug–DNA Interaction Protocols. Humana Press Inc, Totowa, NJ, pp. 51–79. PubMed

He Q., Ohndorf,U.-A. and Lippard,S.J. (2000) Intercalating residues determine the mode of HMG1 domains A and B binding to cisplatin-modified DNA. Biochemistry, 39, 14426–14435. PubMed

Lam W.C., VanderSchans,E.J.C., Sowers,L.C. and Millar,D.P. (1999) Interaction of DNA polymerase I (Klenow fragment) with DNA substrates containing extrahelical bases: Implications for proofreading of frameshift errors during DNA synthesis. Biochemistry, 38, 2661–2668. PubMed

Patel P.H., Suzuki,M., Adman,E., Shinkai,A. and Loeb,L.A. (2001) Prokaryotic DNA polymerase I: Evolution, structure and ‘base flipping’ mechanism for nucleotide selection. J. Mol. Biol., 308, 823–837. PubMed

Johnson K.A. (1993) Conformational coupling in DNA-polymerase fidelity. Annu. Rev. Biochem., 62, 685–713. PubMed

Matsunaga T., Mu,D., Park,C.-H., Reardon,J.T. and Sancar,A. (1995) Human DNA repair excision nuclease. J. Biol. Chem., 270, 20862–20869. PubMed

Buschta-Hedayat N., Buterin,T., Hess,M.T., Missura,M. and Naegeli,H. (1999) Recognition of non-hybridizing base pairs during nucleotide excision repair of DNA. Proc. Natl Acad. Sci. USA, 96, 6090–6095. PubMed PMC

Manley J.L., Fire,A., Cano,A., Sharp,P.A. and Gefter,M.L. (1980) DNA-dependent transcription of adenovirus genes in a soluble whole-cell extract. Proc. Natl Acad. Sci. USA, 77, 3855–3859. PubMed PMC

Reardon J.T., Vaisman,A., Chaney,S.G. and Sancar,A. (1999) Efficient nucleotide excision repair of cisplatin, oxaliplatin and bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts. Cancer Res., 59, 3968–3971. PubMed

Jamieson E.R. and Lippard,S.J. (1999) Structure, recognition and processing of cisplatin-DNA adducts. Chem. Rev., 99, 2467–2498. PubMed

Bellon S.F., Coleman,J.H. and Lippard,S.J. (1991) DNA unwinding produced by site-specific intrastrand cross-links of the antitumor drug cis-diamminedichloroplatinum(II). Biochemistry, 30, 8026–8035. PubMed

Huang H.F., Zhu,L.M., Reid,B.R., Drobny,G.P. and Hopkins,P.B. (1995) Solution structure of a cisplatin-induced DNA interstrand cross-link. Science, 270, 1842–1845. PubMed

Kasparkova J., Novakova,O., Farrell,N. and Brabec,V. (2003) DNA binding by antitumor trans-[PtCl2(NH3)(thiazole)]. Protein recognition and nucleotide excision repair of monofunctional adducts. Biochemistry, 42, 792–800. PubMed

Zehnulova J., Kasparkova,J., Farrell,N. and Brabec,V. (2001) Conformation, recognition by high mobility group domain proteins and nucleotide excision repair of DNA intrastrand cross-links of novel antitumor trinuclear platinum complex BBR3464. J. Biol. Chem., 276, 22191–22199. PubMed

Rhodes D. and Klug,A. (1980) Helical periodicity of DNA determined by enzyme digestion. Nature, 286, 573–578. PubMed

Rice J.A., Crothers,D.M., Pinto,A.L. and Lippard,S.J. (1988) The major adduct of the antitumor drug cis-diamminedichloroplatinum(II) with DNA bends the duplex by 40o toward the major groove. Proc. Natl Acad. Sci. USA, 85, 4158–4161. PubMed PMC

Kostrhunova H. and Brabec,V. (2000) Conformational analysis of site-specific DNA cross-links of cisplatin-distamycin conjugates. Biochemistry, 39, 12639–12649. PubMed

Nielsen P.E. (1990) Chemical and photochemical probing of DNA complexes. J. Mol. Recogit., 3, 1–24. PubMed

Malina J., Hofr,C., Maresca,L., Natile,G. and Brabec,V. (2000) DNA interactions of antitumor cisplatin analogs containing enantiomeric amine ligands. Biophys. J., 78, 2008–2021. PubMed PMC

Wei M., Cohen,S.M., Silverman,A.P. and Lippard,S.J. (2001) Effects of spectator ligands on the specific recognition of intrastrand platinum-DNA cross-links by high mobility group box and TATA-binding proteins. J. Biol. Chem., 276, 38774–38780. PubMed

Ohndorf U.M., Rould,M.A., He,Q., Pabo,C.O. and Lippard,S.J. (1999) Basis for recognition of cisplatin-modified DNA by high-mobility-group proteins. Nature, 399, 708–712. PubMed

Cohen S.M., Mikata,Y., He,Q. and Lippard,S.J. (2000) HMG-domain protein recognition of cisplatin 1,2-intrastrand d(GpG) cross-links in purine-rich sequence contexts. Biochemistry, 39, 11771–11776. PubMed

Kasparkova J., Zehnulova,J., Farrell,N. and Brabec,V. (2002) DNA interstrand cross-links of the novel antitumor trinuclear platinum complex BBR3464. Conformation, recognition by high mobility group domain proteins and nucleotide excision repair. J. Biol. Chem., 277, 48076–48086. PubMed

Stehlikova K., Kostrhunova,H., Kasparkova,J. and Brabec,V. (2002) DNA bending and unwinding due to the major 1,2-GG intrastrand cross-link formed by antitumor cis-diamminedichloroplatinum(II) are flanking-base independent. Nucleic Acids Res., 30, 2894–2898. PubMed PMC

Kasparkova J., Delalande,O., Stros,M., Elizondo-Riojas,M.A., Vojtiskova,M., Kozelka,J. and Brabec,V. (2003) Recognition of DNA interstrand cross-link of antitumor cisplatin by HMGB1 protein. Biochemistry, 42, 1234–1244. PubMed

Comess K.M., Burstyn,J.N., Essigmann,J.M. and Lippard,S.J. (1992) Replication inhibition and translesion synthesis on templates containing site-specifically placed cis-diamminedichloroplatinum(II) DNA adducts. Biochemistry, 31, 3975–3990. PubMed

Suo Z. and Johnson,K. (1998) DNA secondary structure effects on DNA synthesis catalyzed by HIV-1 reverse transcriptase. J. Biol. Chem., 273, 27259–27267. PubMed

Vaisman A., Warren,M.W. and Chaney,S.G. (2001) The effect of DNA structure on the catalytic efficiency and fidelity of human DNA polymerase beta on templates with platinum-DNA adducts. J. Biol. Chem., 276, 18999–19005. PubMed

Suo Z., Lippard,S. and Johnson,K. (1999) Single d(GpG)/cis-diammineplatinum(II) adduct-induced inhibition of DNA polymerization. Biochemistry, 38, 715–726. PubMed

Hubscher U., Nasheuer,H.P. and Syvaoja,J.E. (2000) Eukaryotic DNA polymerases, a growing family. Trends Biochem. Sci., 25, 143–147. PubMed

Steitz T.A. (1999) DNA polymerases: Structural diversity and common mechanisms. J. Biol. Chem., 274, 17395–17398. PubMed

Lone S. and Romano,L.J. (2003) Mechanistic insights into replication across from bulky DNA adducts: A mutant polymerase I allows an N-acetyl-2-aminofluorene adduct to be accommodated during DNA synthesis. Biochemistry, 42, 3826–3834. PubMed

Sancar A. (1996) DNA excision repair. Annu. Rev. Biochem., 65, 43–81. PubMed

Wood R.D. (1996) DNA repair in eukaryotes. Annu. Rev. Biochem., 65, 135–167. PubMed

Reardon J.T. and Sancar,A. (1998) Molecular mechanism of nucleotide excision repair in mammalian cells. In Dizdaroglu,M. and Karakaya,A. (eds), Advances in DNA Damage and Repair. Plenum Publishing Corp., New York, NY, pp. 377–393.

Jones S.L., Hickson,I.D., Harris,A.L. and Harnett,P.R. (1994) Repair of cisplatin–DNA adducts by protein extracts from human ovarian carcinoma. Int. J. Cancer, 59, 388–393. PubMed

Zamble D.B., Mu,D., Reardon,J.T., Sancar,A. and Lippard,S.J. (1996) Repair of cisplatin–DNA adducts by the mammalian excision nuclease. Biochemistry, 35, 10004–10013. PubMed

Moggs J.G., Szymkowski,D.E., Yamada,M., Karran,P. and Wood,R.D. (1997) Differential human nucleotide excision repair of paired and mispaired cisplatin–DNA adducts. Nucleic Acids Res., 25, 480–490. PubMed PMC

Koberle B., Masters,J.R.W., Hartley,J.A. and Wood,R.D. (1999) Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. Curr. Biol., 9, 273–276. PubMed

Li M.J. and Yang,L.Y. (1999) Use of novel plasmid constructs to demonstrate fludarabine triphosphate inhibition of nucleotide excision repair of a site-specific 1,2-d(GpG) intrastrand cisplatin adduct. Int. J. Oncol., 15, 1177–1183. PubMed

Huang J.-C., Svoboda,D.L., Reardon,J.T. and Sancar,A. (1992) Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5′ and the 6th phosphodiester bond 3′ to the photodimer. Proc. Natl Acad. Sci. USA, 89, 3664–3668. PubMed PMC

Calsou P., Frit,P. and Salles,B. (1992) Repair synthesis by human cell extracts in cisplatin-damaged DNA is prefentially determined by minor adducts. Nucleic Acids Res., 20, 6363–6368. PubMed PMC

Buterin T., Hess,M.T., Gunz,D., Geacintov,N.E., Mullenders,L.H. and Naegeli,H. (2002) Trapping of DNA nucleotide excision repair factors by non-repairable carcinogen adducts. Cancer Res., 62, 4229–4235. PubMed

Malina J., Kasparkova,J., Natile,G. and Brabec,V. (2002) Recognition of major DNA adducts of enantiomeric cisplatin analogs by HMG box proteins and nucleotide excision repair of these adducts. Chem. Biol., 9, 629–638. PubMed

Johnson N.P., Butour,J.-L., Villani,G., Wimmer,F.L., Defais,M., Pierson,V. and Brabec,V. (1989) Metal antitumor compounds: The mechanism of action of platinum complexes. Prog. Clin. Biochem. Med., 10, 1–24.

Fuertes M.A., Alonso,C. and Perez,J.M. (2003) Biochemical modulation of cisplatin mechanisms of action: Enhancement of antitumor activity and circumvention of drug resistance. Chem. Rev., 103, 645–662. PubMed

Guo Z.J. and Sadler,P.J. (1999) Metals in medicine. Angew. Chem. Int. Ed., 38, 1513–1531. PubMed

Jordan P. and Carmo-Fonseca,M. (2000) Molecular mechanisms involved in cisplatin cytotoxicity. Cell. Mol. Life Sci., 57, 1229–1235. PubMed PMC

Cohen S.M. and Lippard,S.J. (2001) Cisplatin: From DNA damage to cancer chemotherapy. Prog. Nucleic Acid Res. Mol. Biol., 67, 93–130. PubMed

Wei M., Burenkova,O. and Lippard,S.J. (2003) Cisplatin sensitivity in Hmgb1(–/–) and Hmgb1(+/+) mouse cells. J. Biol. Chem., 278, 1769–1773. PubMed

Ciccarelli R.B., Solomon,M.J., Varshavsky,A. and Lippard,S.J. (1985) In vivo effects of cis- and trans-diamminedichloroplatinum(II) on SV 40 chromosomes: Differential repair, DNA–protein cross-linking and inhibition of replication. Biochemistry, 24, 7533–7540. PubMed

Eastman A. and Barry,M.A. (1987) Interaction of trans-diamminedichloroplatinum(II) with DNA: Formation of monofunctional adducts and their reaction with glutathione. Biochemistry, 26, 3303–3307. PubMed

Bancroft D.P., Lepre,C.A. and Lippard,S.J. (1990) Pt-195 NMR kinetic and mechanistic studies of cis-diamminedichloroplatinum and trans-diamminedichloroplatinum(II) binding to DNA. J. Am. Chem. Soc., 112, 6860–6871.

Lepre C.A. and Lippard,S.J. (1990) Interaction of platinum antitumor compounds with DNA. In Eckstein,F. and Lilley,D.M.J. (eds), Nucleic Acids and Molecular Biology. Springer-Verlag, Berlin, Heidelberg, Germany, Vol. 4, pp. 9–38.

Kelland L.R. (1993) New platinum antitumor complexes. Crit. Rev. Oncol. Hematol., 15, 191–219. PubMed

Leng M., Schwartz,A. and Giraud-Panis,M.J. (2000) Transplatin-modified oligonucleotides as potential antitumor drugs. In Kelland,L.R. and Farrell,N.P. (eds), Platinum-Based Drugs in Cancer Therapy. Humana Press Inc, Totowa, NJ, pp. 63–85.

Zaludova R., Natile,G. and Brabec,V. (1997) The effect of antitumor trans-[PtCl2(E-iminoether)2] on B→Z transition in DNA. Anti-Cancer Drug Des., 12, 295–309. PubMed

Zamble D.B. and Lippard,S.J. (1999) The response of cellular proteins to cisplatin-damaged DNA. In Lippert,B. (ed.), Cisplatin. Chemistry and Biochemistry of a Leading Anticancer Drug. VHCA, WILEY-VCH, Zürich, Weinheim, pp. 73–110.

Kartalou M. and Essigmann,J.M. (2001) Recognition of cisplatin adducts by cellular proteins. Mutation Res., 478, 1–21. PubMed

Zwelling L.A., Anderson,T. and Kohn,K.W. (1979) DNA–protein and DNA interstrand cross-linking by cis- and trans-platinum(II)diamminedichloride in L1210 mouse leukemia cells and relation to cytotoxicity. Cancer Res., 39, 365–369. PubMed

Banjar Z.M., Hnilica,L.S., Briggs,R.C., Stein,J. and Stein,G. (1984) cis- and trans-Diamminedichloroplatinum(II)-mediated cross-linking of chromosomal non-histone proteins to DNA in HeLa cells. Biochemistry, 23, 1921–1926. PubMed

Olinski R., Wedrychovski,A., Schmidt,W.N., Briggs,R.C. and Hnilica,L.S. (1987) In vivo DNA-protein cross-linking by cis- and trans-diamminedichloroplatinum(II). Cancer Res., 47, 201–205. PubMed

Baudin F., Romby,P., Romaniuk,P.J., Ehresmann,B. and Ehresmann,C. (1989) Crosslinking of transcription factor TfIIa to ribosomal 5S RNA from X.laevis by trans-diamminedichloroplatinum(II). Nucleic Acids Res., 17, 10035–10046. PubMed PMC

Miller C.A., Cohen,M.D. and Costa,M. (1991) Complexing of actin and other nuclear proteins to DNA by cis-diamminedichloroplatinum(II) and chromium compounds. Carcinogenesis, 12, 269–276. PubMed

Olinski R.B.R.C. (1991) DNA–protein cross-linking in L1210 cells and resistant to cis-diamminedichloroplatinum(II). Mol. Biol. Rep., 15, 81–86. PubMed

Comess K.M. and Lippard,S.J. (1993) Molecular aspects of platinum-DNA interactions. In Neidle,S. and Waring,M. (eds), Molecular Aspects of Anticancer Drug–DNA Interactions. The MacMillan Press Ltd, Houndmills, UK, Vol. 1, pp. 134–168.

Wozniak K. and Walter,Z. (2000) Induction of DNA–protein cross-links by platinum compounds. Z. Naturforsch. C, 55, 731–736. PubMed

Chichiarelli S., Coppari,S., Turano,C., Eufemi,M., Altieri,F. and Ferraro,A. (2002) Immunoprecipitation of DNA–protein complexes cross-linked by cis-diamminedichloroplatinum. Anal. Biochem., 302, 224–229. PubMed

Plooy A.C.M., Van Dijk,M. and Lohman,P.H.M. (1984) Induction and repair of DNA cross-links in Chinese hamster ovary cells treated with various platinum coordination compounds in relation to platinum binding to DNA, cytotoxicity, mutagenicity and antitumor activity. Cancer Res., 44, 2043–2051. PubMed

Kasparkova J., Marini,V., Najajreh,Y., Gibson,D. and Brabec,V. (2003) DNA binding mode of the cis and trans geometries of new antitumor non-classical platinum complexes containing piperidine, piperazine or 4-picoline ligand in cell-free media. Relations to their activity in cancer cell lines. Biochemistry, 42, 6321–6332. PubMed

Zakovska A., Novakova,O., Balcarova,Z., Bierbach,U., Farrell,N. and Brabec,V. (1998) DNA interactions of antitumor trans-[PtCl2(NH3)(quinoline)]. Eur. J. Biochem., 254, 547–557. PubMed

Brabec V., Neplechova,K., Kasparkova,J. and Farrell,N. (2000) Steric control of DNA interstrand cross-link sites of trans platinum complexes: specificity can be dictated by planar non-leaving groups. J. Biol. Inorg. Chem., 5, 364–368. PubMed

Thermodynamic stability and energetics of DNA duplexes containing major intrastrand cross-links of second-generation antitumor dinuclear Pt(II) complexes

Biophysical studies on the stability of DNA intrastrand cross-links of transplatin

Conformation of DNA GG intrastrand cross-link of antitumor oxaliplatin and its enantiomeric analog

Mechanism of the formation of DNA-protein cross-links by antitumor cisplatin

Conformation, protein recognition and repair of DNA interstrand and intrastrand cross-links of antitumor trans-[PtCl2(NH3)(thiazole)]

Effects of monofunctional adducts of platinum(II) complexes on thermodynamic stability and energetics of DNA duplexes