Using electrophoresis and replication mapping, we show that the presence of DNA adducts of bifunctional antitumor cisplatin or monodentate [PtCl(dien)]Cl (dien = diethylenetriamine) in the substrate DNA inhibits eukaryotic topoisomerase 1 (top1) action, the adducts of cisplatin being more effective. The presence of camptothecin in the samples of platinated DNA markedly enhances effects of Pt-DNA adducts on top1 activity. Interestingly, the effects of Pt-DNA adducts on the catalytic activity of top1 in the presence of camptothecin differ depending on the sequence context. A multiple metallation of the short nucleotide sequences on the scissile strand, immediately downstream of the cleavage site impedes the cleavage by top1. On the other hand, DNA cleavage by top1 at some cleavage sites which were not platinated in their close proximity is notably enhanced as a consequence of global platination of DNA. We suggest that this enhancement of DNA cleavage by top1 may consist in its inability to bind to other cleavage sites platinated in their close neighborhood; thus, more molecules of top1 may become available for cleavage at the sites where top1 normally cleaves and where platination does not interfere.

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

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Kelland L. The resurgence of platinum-based cancer chemotherapy. Nature Rev. Cancer. 2007;7:573–584. PubMed

Jung Y, Lippard SJ. Direct cellular responses to platinum-induced DNA damage. Chem. Rev. 2007;107:1387–1407. PubMed

Brabec V, Kasparkova J. Molecular aspects of resistance to antitumor platinum drugs. Drug Resist. Updates. 2002;5:147–161. PubMed

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

Bouayadi K, Calsou P, Pedrini AM, Salles B. In vitro evolution of cisplatin DNA monoadducts into diadducts is dependent upon superhelical density. Biochem. Biophys. Res. Commun. 1992;189:111–118. PubMed

Vrana O, Boudny V, Brabec V. Superhelical torsion controls DNA interstrand cross-linking by antitumor cis-diamminedichloroplatinum(II) Nucleic Acids Res. 1996;24:3918–3925. PubMed PMC

Coleman LW, Rohr LR, Bronstein IB, Holden JA. Human DNA topoisomerase I: an anticancer drug target present in human sarcomas. Human Pathol. 2002;33:599–607. PubMed

Palumbo M, Gatto B, Moro S, Sissi C, Zagotto G. Sequence-specific interactions of drugs interfering with the topoisomerase-DNA cleavage complex. Biochim. Biophys. Acta. 2002;1587:145–154. PubMed

Ulukan H, Swaan PW. Camptothecins – a review of their chemotherapeutic potential. Drugs. 2002;62:2039–2057. PubMed

Neumann S, Simon H, Zimmer C, Quinones A. The antitumor agent cisplatin inhibits DNA gyrase and preferentially induces gyrB gene expression in Escherichia coli. Biol. Chem. 1996;377:731–739. PubMed

Fukuda M, Nishio K, Kanzawa F, Ogasawara H, Ishida T, Arioka H, Bojanowski K, Oka M, Saijo N. Synergism between cisplatin and topoisomerase I inhibitors, NB-506 and SN-38, in human small cell lung cancer cells. Cancer Res. 1996;56:789–793. PubMed

Masumoto N, Nakano S, Esaki T, Fujishima H, Tatsumoto T, Niho Y. Inhibition of cis-diamminedichloroplatinum (II)-induced DNA interstrand cross-link removal by 7-ethyl-10-hydroxy-camptothecin in HST-1 human squamous-carcinoma cells. Int. J. Cancer. 1995;62:70–75. PubMed

Kanzawa F, Koizumi F, Koh Y, Nakamura T, Tatsumi Y, Fukumoto H, Saijo N, Yoshioka T, Nishio K. In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction. Clin. Cancer Res. 2001;7:202–209. PubMed

Guichard S, Arnould S, Hennebelle I, Bugat R, Canal P. Combination of oxaliplatin and irinotecan on human colon cancer cell lines: activity in vitro and in vivo. Anti-Cancer Drugs. 2001;12:741–751. PubMed

Aoe K, Kiura K, Ueoka H, Tabata M, Chikamori M, Kohara H, Harada M, Tanimoto M. Cisplatin down-regulates topoisomerase I activity in lung cancer cell lines. Anticancer Res. 2004;24:3893–3897. PubMed

Tanaka R, Ariyama H, Qin BL, Shibata Y, Takii Y, Kusaba H, Baba E, Mitsugi K, Harada M, Nakano S. Synergistic interaction between oxaliplatin and SN-38 in human gastric cancer cell lines in vitro. Oncol. Rep. 2005;14:683–688. PubMed

Kobayashi S, Furukawa M, Dohi C, Hamashima H, Arai T, Tanaka A. Topology effect for DNA structure of cisplatin: topological transformation of cisplatin-closed circular DNA adducts by DNA topoisomerase I. Chem. Pharm. Bull. 1999;47:783–790. PubMed

van Waardenburg RCAM, de Jong LA, van Eijndhoven MAJ, Verseyden C, Pluim D, Jansen LET, Bjornsti M-A, Schellens JHM. Platinated DNA adducts enhance poisoning of DNA topoisomerase I by camptothecin. J. Biol. Chem. 2004;279:54502–54509. PubMed

Fichtinger-Schepman AMJ, Van der Veer JL, Den Hartog JHJ, Lohman PHM, Reedijk J. Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitation. Biochemistry. 1985;24:707–713. PubMed

Brabec V, Kleinwächter V, Butour JL, Johnson NP. Biophysical studies of the modification of DNA by antitumour platinum coordination complexes. Biophys. Chem. 1990;35:129–141. PubMed

Andersen AH, Gocke E, Bonven BJ, Nielsen OF, Westergaard O. Topoisomerase-I has a strong binding preference for a conserved hexadecameric sequence in the promotor region of the ribosomal-RNA gene from Tetrahymena-Pyriformis. Nucleic Acids Res. 1985;13:1543–1557. PubMed PMC

Bonven BJ, Gocke E, Westergaard O. A high-affinity topoisomerase-1 binding sequence is clustered at DNase-1 hypersensitive sites in Tetrahymena R-chromatin. Cell. 1985;41:541–551. PubMed

Pommier Y, Kohlhagen G, Kohn KW, Leteurtre F, Wani MC, Wall ME. Interaction of an alkylating camptothecin derivative with a DNA-base at topoisomerase I-DNA cleavage sites. Proc. Natl Acad. Sci. USA. 1995;92:8861–8865. PubMed PMC

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

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

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

Maxam AM, Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65:499–560. PubMed

Novakova O, Kasparkova J, Vrana O, van Vliet PM, Reedijk J, Brabec V. Correlation between cytotoxicity and DNA binding of polypyridyl ruthenium complexes. Biochemistry. 1995;34:12369–12378. PubMed

Keck MV, Lippard SJ. Unwinding of supercoiled DNA by platinum ethidium and related complexes. J. Am. Chem. Soc. 1992;114:3386–3390.

Verma RP, Hansch C. Camptothecins: A SAR/QSAR study. Chem. Rev. 2009;109:213–235. PubMed

Nagarajan M, Morrell A, Ioanoviciu A, Antony S, Kohlhagen G, Agama K, Hollingshead M, Pommier Y, Cushman M. Synthesis and evaluation of indenoisoquinoline topoisomerase I inhibitors substituted with nitrogen heterocycles. J. Med. Chem. 2006;49:6283–6289. PubMed PMC

Pourquier P, Pilon AA, Kohlhagen G, Mazumder A, Sharma A, Pommier Y. Trapping of mammalian topoisomerase I and recombinations induced by damaged DNA containing nicks or gaps – importance of DNA end phosphorylation and camptothecin effects. J. Biol. Chem. 1997;272:26441–26447. PubMed

Pourquier P, Ueng LM, Fertala J, Wang D, Park HJ, Essigmann JM, Bjornsti MA, Pommier Y. Induction of reversible complexes between eukaryotic DNA topoisomerase I and DNA-containing oxidative base damages – 7,8-dihydro-8-oxoguanine and 5-hydroxycytosine. J. Biol. Chem. 1999;274:8516–8523. PubMed

Redinbo MR, Champoux JJ, Hol WGJ. Novel insights into catalytic mechanism from a crystal structure of human topoisomerase I in complex with DNA. Biochemistry. 2000;39:6832–6840. PubMed

Pommier Y, Kohlhagen G, Laco GS, Kroth H, Sayer JM, Jerina DM. Different effects on human topoisomerase I by minor groove and intercalated deoxyguanosine adducts derived from two polycyclic aromatic hydrocarbon diol epoxides at or near a normal cleavage site. J. Biol. Chem. 2002;277:13666–13672. PubMed

Zaludova R, Kleinwächter V, Brabec V. The effect of ionic strength on melting of DNA modified by platinum(II) complexes. Biophys. Chem. 1996;60:135–142. PubMed

Johnson NP, Macquet J-P, Wiebers JL, Monsarrat B. Structures of adducts formed between [Pt(dien)Cl]Cl and DNA in vitro. Nucleic Acids Res. 1982;10:5255–5271. PubMed PMC

Cohen SM, Mikata Y, He Q, Lippard SJ. HMG-Domain protein recognition of cisplatin 1,2-intrastrand d(GpG) cross-links in purine-rich sequence contexts. Biochemistry. 2000;39:11771–11776. PubMed

Lock RB, Ross WE. DNA topoisomerases in cancer therapy. Anti-Cancer Drug Des. 1987;2:151–164. PubMed

Chen AY, Liu LF. DNA topoisomerases:Essential enzymes and lethal targets. Annu. Rev. Pharmacol. Toxicol. 1994;34:191–218. PubMed

Gupta M, Fujimori A, Pommier Y. Eukaryotic DNA topoisomerases I. Biochim. Biophys. Acta. 1995;1262:1–14. PubMed

Capranico G, Binaschi M. DNA sequence selectivity of topoisomerases and topoisomerase poisons. Biochim. Biophys. Acta. 1998;1400:185–194. PubMed

Liu LF, Desai SD, Li TK, Mao Y, Sun M, Sim SP. Mechanism of action of camptothecin. Ann. NY Acad. Sci. 2000;922:1–10. PubMed

Been MD, Burgess RR, Champoux JJ. Nucleotide sequence preference at rat liver and wheat germ type 1 DNA topoisomerase breakage sites in duplex SV40 DNA. Nucleic Acids Res. 1984;12:3097–3114. PubMed PMC

Jaxel C, Capranico G, Kerrigan D, Kohn K, Pommier Y. Effect of local DNA sequence on topoisomerase I cleavage in the presence or absence of camptothecin. J. Biol. Chem. 1991;266:20418–20423. PubMed

Tanizawa A, Kohn KW, Pommier Y. Induction of cleavage in topoisomerase I c-DNA by topoisomerase I enzymes from calf thymus and wheat germ in the presence and absence of camptothecin. Nucleic Acids Res. 1993;21:5157–5166. PubMed PMC

Cohen GL, Ledner JA, Bauer WR, Ushay HM, Caravana C, Lippard SJ. Sequence dependent binding of cis-dichlorodiammineplatinum(II) to DNA. J. Am. Chem. Soc. 1980;102:2487–2488.

Tullius TD, Lippard SJ. Ethidium bromide changes the nuclease-sensitive DNA binding sites of the antitumor drug cis-diamminedichloroplatinum(II) Proc. Natl Acad. Sci. USA. 1982;79:3489–3492. PubMed PMC

Kjeldsen E, Svejstrup JQ, Gromova II, Alsner J, Westergaard O. Camptothecin inhibits both the cleavage and religation reactions of eukaryotic DNA topoisomerase I. J. Mol. Biol. 1992;228:1025–1030. PubMed

Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WGJ. Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science. 1998;279:1504–1513. PubMed

Ward B, Rehfuss R, Goodisman J, Dabrowiak JC. Rate enhancements in the DNase I footprinting experiment. Nucleic Acids Res. 1988;16:1359–1369. PubMed PMC

Goodisman J, Dabrowiak JC. Structural changes and enhancements in DNase I footprinting experiments. Biochemistry. 1992;31:1058–1064. PubMed

Jamieson ER, Lippard SJ. Structure, recognition, and processing of cisplatin-DNA adducts. Chem. Rev. 1999;99:2467–2498. PubMed