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. 1998 Sep 1;26(17):3933–3939. doi: 10.1093/nar/26.17.3933

The interaction of DNA-targeted platinum phenanthridinium complexes with DNA.

J Whittaker 1, W D McFadyen 1, G Wickham 1, L P Wakelin 1, V Murray 1
PMCID: PMC147812  PMID: 9705500

Abstract

Cisplatin analogues were synthesised that consisted of platinum(II) diamine complexes tethered via a polymethylene chain ( n = 3, 5, 8 and 10) to a phenanthridinium cation. Both chloro and iodo leaving groups were examined. DNA adduct formation was quantitatively analysed using a linear amplification system with the plasmid pGEM-3Zf(+). This system utilised Taq DNA polymerase to extend from an oligonucleotide primer to the damage site. This damage site inhibited the extension of the DNA polymerase. The products were electrophoresed on a DNA sequencing gel enabling adduct formation to be determined at base pair resolution. The damage intensity at each site was determined by densitometry. The platinum phenanthridinium complexes were shown to damage DNA at shorter incubation times than cisplatin. To produce similar levels of damage, an 18 h incubation was required for cisplatin compared to 30 min for the n = 3 platinum phenanthridinium complexes; this indicates that the intercalating chromophore causes a large increase in the rate of platination. A reaction mechanism involving direct displacement of the chloride by the N-7 of guanine may account for the rate increase. These results indicate that further development of these compounds could lead to more effective cancer chemotherapeutic agents.

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Selected References

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  1. Andrews P. A., Murphy M. P., Howell S. B. Differential potentiation of alkylating and platinating agent cytotoxicity in human ovarian carcinoma cells by glutathione depletion. Cancer Res. 1985 Dec;45(12 Pt 1):6250–6253. [PubMed] [Google Scholar]
  2. Christian M. C. The current status of new platinum analogs. Semin Oncol. 1992 Dec;19(6):720–733. [PubMed] [Google Scholar]
  3. Comess K. M., Burstyn J. N., Essigmann J. M., Lippard S. J. Replication inhibition and translesion synthesis on templates containing site-specifically placed cis-diamminedichloroplatinum(II) DNA adducts. Biochemistry. 1992 Apr 28;31(16):3975–3990. doi: 10.1021/bi00131a013. [DOI] [PubMed] [Google Scholar]
  4. Dabrowiak J. C., Bradner W. T. Platinum antitumour agents. Prog Med Chem. 1987;24:129–158. doi: 10.1016/s0079-6468(08)70421-1. [DOI] [PubMed] [Google Scholar]
  5. Denny W. A. DNA-intercalating ligands as anti-cancer drugs: prospects for future design. Anticancer Drug Des. 1989 Dec;4(4):241–263. [PubMed] [Google Scholar]
  6. Fan J. Y., Valu K. K., Woodgate P. D., Baguley B. C., Denny W. A. Aniline mustard analogues of the DNA-intercalating agent amsacrine: DNA interaction and biological activity. Anticancer Drug Des. 1997 Apr;12(3):181–203. [PubMed] [Google Scholar]
  7. Fram R. J., Woda B. A., Wilson J. M., Robichaud N. Characterization of acquired resistance to cis-diamminedichloroplatinum (II) in BE human colon carcinoma cells. Cancer Res. 1990 Jan 1;50(1):72–77. [PubMed] [Google Scholar]
  8. Gourdie T. A., Valu K. K., Gravatt G. L., Boritzki T. J., Baguley B. C., Wakelin L. P., Wilson W. R., Woodgate P. D., Denny W. A. DNA-directed alkylating agents. 1. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the reactivity of the mustard. J Med Chem. 1990 Apr;33(4):1177–1186. doi: 10.1021/jm00166a015. [DOI] [PubMed] [Google Scholar]
  9. Gralla J. D., Sasse-Dwight S., Poljak L. G. Formation of blocking lesions at identical DNA sequences by the nitrosourea and platinum classes of anticancer drugs. Cancer Res. 1987 Oct 1;47(19):5092–5096. [PubMed] [Google Scholar]
  10. Grimaldi K. A., McAdam S. R., Souhami R. L., Hartley J. A. DNA damage by anti-cancer agents resolved at the nucleotide level of a single copy gene: evidence for a novel binding site for cisplatin in cells. Nucleic Acids Res. 1994 Jun 25;22(12):2311–2317. doi: 10.1093/nar/22.12.2311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Harrap K. R. Initiatives with platinum- and quinazoline-based antitumor molecules--Fourteenth Bruce F. Cain Memorial Award Lecture. Cancer Res. 1995 Jul 1;55(13):2761–2768. [PubMed] [Google Scholar]
  12. Holley J. L., Mather A., Wheelhouse R. T., Cullis P. M., Hartley J. A., Bingham J. P., Cohen G. M. Targeting of tumor cells and DNA by a chlorambucil-spermidine conjugate. Cancer Res. 1992 Aug 1;52(15):4190–4195. [PubMed] [Google Scholar]
  13. Lambert B., Jestin J. L., Bréhin P., Oleykowski C., Yeung A. T., Mailliet P., Prétot C., Le Pecq J. B., Jacquemin-Sablon A., Chottard J. C. Binding of the Escherichia coli UvrAB proteins to the DNA mono- and diadducts of cis-[N-2-amino-N-2-methylamino-2,2,1-bicycloheptane]dichloroplatinum(II ) and cisplatin. Analysis of the factors controlling recognition and proof of monoadduct-mediated UvrB-DNA cross-linking. J Biol Chem. 1995 Sep 8;270(36):21251–21257. doi: 10.1074/jbc.270.36.21251. [DOI] [PubMed] [Google Scholar]
  14. Lee H. H., Palmer B. D., Baguley B. C., Chin M., McFadyen W. D., Wickham G., Thorsbourne-Palmer D., Wakelin L. P., Denny W. A. DNA-directed alkylating agents. 5. Acridinecarboxamide derivatives of (1,2-diaminoethane)dichloroplatinum(II). J Med Chem. 1992 Aug 7;35(16):2983–2987. doi: 10.1021/jm00094a008. [DOI] [PubMed] [Google Scholar]
  15. Loehrer P. J., Einhorn L. H. Drugs five years later. Cisplatin. Ann Intern Med. 1984 May;100(5):704–713. doi: 10.7326/0003-4819-100-5-704. [DOI] [PubMed] [Google Scholar]
  16. Murray V. Improved double-stranded DNA sequencing using the linear polymerase chain reaction. Nucleic Acids Res. 1989 Nov 11;17(21):8889–8889. doi: 10.1093/nar/17.21.8889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Murray V., Motyka H., England P. R., Wickham G., Lee H. H., Denny W. A., McFadyen W. D. An investigation of the sequence-specific interaction of cis-diamminedichloroplatinum(II) and four analogues, including two acridine-tethered complexes, with DNA inside human cells. Biochemistry. 1992 Dec 1;31(47):11812–11817. doi: 10.1021/bi00162a020. [DOI] [PubMed] [Google Scholar]
  18. Murray V., Motyka H., England P. R., Wickham G., Lee H. H., Denny W. A., McFadyen W. D. The use of Taq DNA polymerase to determine the sequence specificity of DNA damage caused by cis-diamminedichloroplatinum(II), acridine-tethered platinum(II) diammine complexes or two analogues. J Biol Chem. 1992 Sep 15;267(26):18805–18809. [PubMed] [Google Scholar]
  19. Murray V., Whittaker J., Temple M. D., McFadyen W. D. Interaction of 11 cisplatin analogues with DNA: characteristic pattern of damage with monofunctional analogues. Biochim Biophys Acta. 1997 Nov 20;1354(3):261–271. doi: 10.1016/s0167-4781(97)00087-0. [DOI] [PubMed] [Google Scholar]
  20. Palmer B. D., Lee H. H., Johnson P., Baguley B. C., Wickham G., Wakelin L. P., McFadyen W. D., Denny W. A. DNA-directed alkylating agents. 2. Synthesis and biological activity of platinum complexes linked to 9-anilinoacridine. J Med Chem. 1990 Nov;33(11):3008–3014. doi: 10.1021/jm00173a015. [DOI] [PubMed] [Google Scholar]
  21. Pinto A. L., Lippard S. J. Sequence-dependent termination of in vitro DNA synthesis by cis- and trans-diamminedichloroplatinum (II). Proc Natl Acad Sci U S A. 1985 Jul;82(14):4616–4619. doi: 10.1073/pnas.82.14.4616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Podyminogin M. A., Meyer R. B., Jr, Gamper H. B. RecA-catalyzed, sequence-specific alkylation of DNA by cross-linking oligonucleotides. Effects of length and nonhomologous base substitutions. Biochemistry. 1996 Jun 4;35(22):7267–7274. doi: 10.1021/bi9529465. [DOI] [PubMed] [Google Scholar]
  23. Ponti M., Forrow S. M., Souhami R. L., D'Incalci M., Hartley J. A. Measurement of the sequence specificity of covalent DNA modification by antineoplastic agents using Taq DNA polymerase. Nucleic Acids Res. 1991 Jun 11;19(11):2929–2933. doi: 10.1093/nar/19.11.2929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Prakash A. S., Denny W. A., Gourdie T. A., Valu K. K., Woodgate P. D., Wakelin L. P. DNA-directed alkylating ligands as potential antitumor agents: sequence specificity of alkylation by intercalating aniline mustards. Biochemistry. 1990 Oct 23;29(42):9799–9807. doi: 10.1021/bi00494a007. [DOI] [PubMed] [Google Scholar]
  25. Royer-Pokora B., Gordon L. K., Haseltine W. A. Use of exonuclease III to determine the site of stable lesions in defined sequences of DNA: the cyclobutane pyrimidine dimer and cis and trans dichlorodiammine platinum II examples. Nucleic Acids Res. 1981 Sep 25;9(18):4595–4609. doi: 10.1093/nar/9.18.4595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sun N. E., Shen B. H., Zhou J. M., Yuan J., Xu X. X., Zhu D. X., Han K. K. An efficient method for large-scale isolation of plasmid DNAs by heat-alkali co-denaturation. DNA Cell Biol. 1994 Jan;13(1):83–86. doi: 10.1089/dna.1994.13.83. [DOI] [PubMed] [Google Scholar]
  27. Temple M. D., Cairns M. J., Denny W. A., Murray V. Protein-DNA interactions in the human beta-globin locus control region hypersensitive site-2 as revealed by four nitrogen mustards. Nucleic Acids Res. 1997 Aug 15;25(16):3255–3260. doi: 10.1093/nar/25.16.3255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wickham G., Prakash A. S., Wakelin L. P., McFadyen W. D. DNA-binding properties and antitumour activity of monofunctional alkylating groups attached to the DNA-intercalating chromophore phenanthridine: n-bromoalkylphenanthridinium bromides. Biochim Biophys Acta. 1991 Apr 9;1073(3):528–537. doi: 10.1016/0304-4165(91)90226-7. [DOI] [PubMed] [Google Scholar]
  29. Zunino F., Savi G., Pasini A. Synthesis and antitumor activity of a platinum (II)-doxorubicin complex. Cancer Chemother Pharmacol. 1986;18(2):180–182. doi: 10.1007/BF00262293. [DOI] [PubMed] [Google Scholar]

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