This article delineates the chemistry of platinum antitumor drugs and related compounds with DNA. The evidence that DNA is primary target for cisplatin has been presented in detail elsewhere.1 Displayed in Figure 1 are structural representations of the platinum complexes to be discussed. Cisplatin and carboplatin are the only two currently approved for use clinically. They follow the classical structure-function relationships,2 being able to form cross-links at two cis positions in their coordination spheres, in contrast to the monofunctional complexes [Pt(dien)Cl]+ and [Pt(NH3)3Cl]+, and the bifunctional trans-[Pt(NH3)2Cl2] analogue. Two promising candidates for clinical trials are included, “triamine” complexes [Pt(NH3)2(4-X-py)Cl]+ (X = Me, Br) which violate two of the classical rules in being cationic and monofunctional,3 and a complex, cis-[Pt(NH3)(C6H11NH2)Cl2], that is a likely metabolite of a new class of orally active antitumor platinum(IV) compounds.4 The other compounds all have the ability to bind to DNA in whole or in part by intercalation. Since some of the compounds used in combination chemotherapy with cisplatin are intercalators, bleomycin being one example, it is important to understand their ternary interactions with DNA. Only the results of experiments carried out in vitro are included in the discussion, although we caution that there will be some differences from the reactions that take place in living cells.5


Ternary Complex Platinum Complex Platinum Compound Platinum Atom Hinge Joint 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    A. L. Pinto and S. J. Lippard, Binding of the antitumor drug cis-diamminedichloroplatinum(II) (cisplatin) to DNA, Biochim. Biophys. Acta 780:167 (1985).PubMedGoogle Scholar
  2. 2.
    M. J. Cleare and J.D. Hoeschele, Antitumor activity of group VIII transition metal complexes. I. Platinum(II) complexes, Bioinorg. Chem., 2: 187 (1973).CrossRefGoogle Scholar
  3. 3.
    L. S. Hollis, A. R. Amundsen, and E. W. Stern, Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor) Cl]+, J. Med. Chem., 32:128 (1989).PubMedCrossRefGoogle Scholar
  4. 4.
    C. M. Giandomenico, M. J. Abrams, B. A. Murrer, and J. F. Vollano, Synthesis and reactions of a new class of orally active platinum(IV) antitumor complexes, this volume.Google Scholar
  5. 5.
    S. K. Mauldin, G. Gibbons, S. D. Wyrick, and S. G. Chaney, Intracellular biotransformations of platinum compounds with the 1,2-diaminocyclohexane carrier ligand in the L1210 cell line, Cancer Research, 48: 5136 (1988).PubMedGoogle Scholar
  6. 6.
    C. A. Lepre and S. J. Lippard, Interaction of platinum antitumor compounds with DNA, Nucl. Acids Res. and Mol. Biol., 4:9 (1990).CrossRefGoogle Scholar
  7. 7.
    S. L. Bruhn, J. H. Toney, and S. J. Lippard, Biological Processing of DNA Modified by Platinum Compounds, Prog. Inorg. Chem., 38:477 (1990).CrossRefGoogle Scholar
  8. 8.
    W. I. Sundquist, D. P. Bancroft, L. Chassot, and S. J. Lippard, DNA promotes the reaction of cis-diamminedichloroplatinum(II) with the exocyclic amino groups of ethidium bromide, J. Am. Chem. Soc., 112:6960 (1990).CrossRefGoogle Scholar
  9. 9.
    D. P. Bancroft, C. A. Lepre, and S. J. Lippard, 195Pt NMR kinetic and mechanistic studies of cis-and trans-diamminedichloroplatinum(II) binding to DNA, J. Am. Chem. Soc., 112:6960 (1990).CrossRefGoogle Scholar
  10. 10.
    K. M. Comess, C. E. Costello, and S. J. Lippard, Identification and characterization of a novel linkage isomerization in the reaction of trans-diamminedichloroplatinum(II) with 5′-d(TCTACGCGTTCT), Biochemistry, 29:2102 (1990).PubMedCrossRefGoogle Scholar
  11. 11.
    K. M. Comess, unpublished results.Google Scholar
  12. 12.
    S. E. Sherman and S. J. Lippard, Structural aspects of platinum anticancer drug interactions with DNA, Chem. Rev., 87:1153 (1987).CrossRefGoogle Scholar
  13. 13.
    S. E. Sherman, D. Gibson, A. H.-J. Wang, and S. J. Lippard, Crystal and molecular structure of cis-[Pt(NH3)2d(pGpG)], the principal adduct formed by cis-diamminedichloroplatinum(II) with DNA. J. Am. Chem. Soc.. 110:7368, 1988.CrossRefGoogle Scholar
  14. 14.
    S. F. Bellon and S. J. Lippard, unpublished results.Google Scholar
  15. 15.
    With D. Patel and colleagues, Columbia University.Google Scholar
  16. 16.
    J. F. Hartwig and S. J. Lippard, unpublished results.Google Scholar
  17. 17.
    C. A. Lepre, K. G. Strothkamp, and S. J. Lippard, Synthesis and 1H NMR spectroscopic characterization of trans-[Pt(NH3)2d(ApGpGpCpCpT)-N7-A(1),N7-G(3)], Biochemistry, 26:5651 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    J. L. van der Veer, G. J. Ligtvoet, H. van den Elst, and J. Reedijk, trans-Diamminedichloroplatinumt(II) can chelate d(GpTpG) via both guanines in a similar fashion as the cis isomer, J. Am. Chem. Soc., 108:3860 (1986).CrossRefGoogle Scholar
  19. 19.
    L. S. Hollis, W. I. Sundquist, J. N. Burstyn, W. J. Heiger-Bernays, S. F. Bellon, K. J. Ahmed. A. R. Amundsen, E. W. Stern and S. J. Lippard, Mechanistic studies of a novel class of trisubstituted platinum(II) antitumor agents, Cancer Research, in press.Google Scholar
  20. 20.
    E. L. M. Lempers, M. J. Bloemink, J. Brouwer, Y. Kidani, and J. Reedijk, The new antitumor compound, cis-[Pt(NH3)2(4-methylpyridine)Cl]Cl, does not form N7,N7-d(GpG) chelates with DNA. An unexpected preference for platinum binding at the 5′G in d(GpG). J. Inorg. Biochem., 40: 23 (1990).PubMedCrossRefGoogle Scholar
  21. 21.
    S. J. Lippard, H. M. Ushay, C. M. Merkel, and M. C. Poirier, Use of antibodies to probe the stereochemistry of antitumor platinum drug binding to DNA, Biochemistry, 22:5165 (1983).CrossRefGoogle Scholar
  22. 22.
    W. I. Sundquist, S. J. Lippard, and B. D. Stollar. Monoclonal antibodies to DNA modified with cis-or trans-diamminedichloroplatinum(II). Proc. Natl. Acad. Sci. U.S.A.. 84:8225, 1987.PubMedCrossRefGoogle Scholar
  23. 23.
    J. A. Rice, D. M. Pinto, A. L. Pinto, and S. J. Lippard, The major adduct of the antitumor drug cis-diamminedichloroplatinum(II) with DNA bends the duplex by ~40° toward the major groove, Proc Natl. Acad. Sci. U.S.A., 85:4158 (1988).PubMedCrossRefGoogle Scholar
  24. 24.
    S. F. Bellon and S. J. Lippard, Bending studies of DNA site-specifically modified by cisplatin, trans-diamminedichloroplatinum(II), and cis-[Pt(NH3)2(N3-cytosine)Cl]+, Biophys. Chem., 35:179 (1990).PubMedCrossRefGoogle Scholar
  25. 25.
    S. F. Bellon and S. J. Lippard, unpublished results.Google Scholar
  26. 26.
    A. L. Pinto, L. J. Naser, J. M. Essigmann, and S. J. Lippard, Site-specifically platinated DNA, a new probe of the biological activity of platinum anticancer drugs. J. Am. Chem. Soc. 108:7405 (1986).CrossRefGoogle Scholar
  27. 27.
    M. Anin and M. Leng, Distortions induced in double-stranded oligonucleotides by the binding of cis-12 or trans-diammine-dichloroplatinum(II) to the d(GTG) sequence, Nucleic Acids Res., 18:4395 (1990).PubMedCrossRefGoogle Scholar
  28. 28.
    K. W. Jennette, S. J. Lippard, G. A Vassiliades, and W. R. Bauer, Metallointercalation reagents. 2-Hydroxyethanethiolate(2,2′,2″-terpyridine)platinum(II) monocation binds strongly to DNA by intercalation, Proc. Natl. Acad. Sci. U.S.A., 71:3839 (1974).PubMedCrossRefGoogle Scholar
  29. 29.
    M. Howe-Grant, K. Wu, W. R. Bauer, and S. J. Lippard, Binding of platinum and palladium metallointercalation reagents and antitumor drugs to closed and open DNAs, Biochemistry, 15:4339 (1976).PubMedCrossRefGoogle Scholar
  30. 30.
    A. H. J. Wang, J. Nathans, G. van der Marel, J. H. van Boom, and A. Rich, Molecular structure of a double helical DNA fragment-intercalator complex: deoxy CpG and a terpyridine platinum compound, Nature, 276:471 (1978).PubMedCrossRefGoogle Scholar
  31. 31.
    J-P. Macquet and J-L. Butour, DNA-platinun interactions, J. Clin. Hematol. Oncol., 7:469 (1977).Google Scholar
  32. 32.
    T. D. Tullius and S. J. Lippard, Ethidium bromide changes the nuclease-sensitive DNA binding sites of the antitumor drug cis-diamminedichloroplatinum(II), Proc. Natl. Acad. Sci. U.S.A., 79:3489 (1982).PubMedCrossRefGoogle Scholar
  33. 33.
    C. M. Merkel and S. J. Lippard, Ethidium bromide alters the binding mode of cis-diamminedichloroplatinum(II) to pBR322 DNA, Cold Spring Harbor Symp.Quant. Biol. 47:355 (1983).PubMedCrossRefGoogle Scholar
  34. 34.
    J-M. Malinge and M. Leng, Reaction of nucleic acids and cis-diamminedichloroplatinum(II) in the presence of intercalating agents, Proc. Natl. Acad. Sci. U.S.A., 83:6317 (1986).PubMedCrossRefGoogle Scholar
  35. 35.
    D. P. Bancroft, W. I. Sundquist, L. Chassot, and S. J. Lippard, unpublished results.Google Scholar
  36. 36.
    B. E. Bowler, K. J. Ahmed, W. I. Sundquist, L. S. Hollis, E. E. Whang, and S. J. Lippard, Synthesis, characterization, and DNA-binding properties of (1,2-diaminoethane)platinum(II) complexes linked to the DNA intercalator acridine orange by trimethylene and hexamethylene chains, J. Am. Chem. Soc. 111:1299 (1989).CrossRefGoogle Scholar
  37. 37.
    B. A. Donahue, M. Augot, S. F. Bellon, D. K. Treiber, J. H. Toney, S. J. Lippard, and J. M. Essigmann, Characterization of a DNA damage-recognition protein from mammalian cells that bind specifically to intrastrand d(GpG) and d(ApG) DNA adducts of the anticancer drug cisplatin, Biochemistry, 29:5872 (1990).PubMedCrossRefGoogle Scholar
  38. 38.
    J. H. Toney, B. A. Donahue, P. J. Kellett, S. L. Bruhn, J. M. Essigmann, and S. J. Lippard, Isolation of cDNAs encoding a human protein that binds selectively to DNA modified by the antitumor drug cis-diamminedichloroplatinum(II), Proc. Natl. Acad. Sci. U.S.A., 86:8328 (1989).PubMedCrossRefGoogle Scholar
  39. 39.
    B. A. Donahue, S. L. Bellon, S. J. Lippard, and J. M. Essigmann, this volume.Google Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Stephen J. Lippard
    • 1
  1. 1.Department of ChemistryMassachusetts Institute of ChemistryCambridgeUSA

Personalised recommendations