Advertisement

New Insights About the Interaction of Cisplatinum with Intracellular Components

  • Jan Reedijk

Summary

The now classic antitumor compound cis-PtCl2(NH3)2 (abbreviated as cisPt) is known to react with cellular components, such as DNA and proteins. Initially most attention was focussed on the binding of cisPt with DNA, as the antitumor properties are likely to be based upon selective interaction with DNA. After injection in the blood, the drug is transported through the body, probably entering both normal and tumor cells. Inside the cell relatively slow hydrolysis occurs, followed by binding to DNA and possible other targets.

To understand the details of the DNA binding, studies of the binding of platinum compounds with relatively small single-stranded and double-stranded oligonucleotides under a variety of in-vitro conditions have been studied and the results will be summarized. Other possible binding sites for platinum compounds in cells are those at proteins; these are generally believed to be the most likely origin of the several toxic side effects of cisPt and the several derivatives. In fact significant amounts of administrated cisPt are lost as a result of binding to proteins; some of these bonds can be “rescued” by certain agents, like thiourea.

To explore this type of protein-binding reactions a variety of Pt amine compounds (including the inactive trans isomer of cisPt and also the reference compound [PtCl(dien)]Cl) have been reacted with synthetic peptides and with proteins. To study the competition between proteins and nucleic acids, in-vitro reactions have been carried out between Pt compounds and nucleopeptides. It has been found that the degree of hydrolysis of cisPt determines the rate of binding to DNA (at guanine-N7) and to S-donor atoms (most rapidly at thioethers) in proteins and peptides.

Using advanced NMR techniques, in combination with spectroscopy and X-ray diffraction studies, the structures and conformations of the obtained Pt-DNA adducts and Pt-peptide adducts have been determined. The results are of importance for a better understanding of the mechanism of action for cisPt and related compounds, and will also be used to make predictions for possible third-generation Pt compounds.

During the last decades cis-diamminedichloroplatinum(II) has emerged as a classical compound in antitumor drug therapy. It has been generally accepted that binding of the compound to DNA is a major requirement for its biological activity, and as a result many scientists have focussed their attention especially on platinum-DNA interactions. However, also Pt-protein interactions and especially with S-containing biomolecules are of great importance, as will be shown below.

The compound [cis-PtCl2(NH3)2], often abbreviated as cisplatin, cisplatinum, cis-DDP, DDP, c-DDP, or cis-Pt, has been known since the last century. Renewed interest in cisplatin and in its trans isomer has resulted from experiments by Rosenberg1–6, who investigated the role of electric fields on cell division of cultured bacterial cells. The field generated between platinum electrodes seemed to stop cell division without hampering cell growth, which later turned out to be the result of small amounts of dissolved compounds like [cis-PtCl4(NH3)2], formed during electrolysis by interaction of the electrolyte (NH4Cl) and the “inert” Pt electrodes2.

Later many other Pt(II) and Pt(IV) compounds were found to show similar effects on bacterial growth3. Surprisingly, only the cis- and not the trans-isomer appeared to be effective. The antitumor activity of these and other platinum compounds have been studied. In particular on tumors induced in animals, such as Sarcoma 180 and Leukemia L1210 in mice4,5, [cis-PtCl2(NH3)2] turned out to be a very active compound against a variety of animal tumors6.

For testicular and ovarian cancer the progress in the curing of these tumor types, effected by the use of cis-Pt is spectacular7 and especially for early recognized testicular cancer, the curing rate is approaching 100%.

A great variety of other platinum compounds has been synthesized since then by many chemists and these have been tested for antitumor activity. Basic criteria for the structure and the reactivity of such new compounds have been published by several groups8. Most active compounds have two leaving groups, although recently a few exceptions of antitumor active Pt compounds have been reported, which seem to deviate from these empirical rules in having only have one anionic ligand. Examples of promising compounds are [Pt(diam) (R’R’’ SO)Cl]NO3 9 and [cis-Pt(NH3)2(N-het)Cl]Cl10. During the last few years other interesting and new approaches in the design of antitumor drugs have developed; a variety of platinum complexes are becoming available, having the following characteristics:
  1. (1)

    They contain carrier molecules as ligands for achieving higher drug concentrations, or slower release in tumor tissues11.

     
  2. (2)

    They contain also other chemotherapeutic agents, like intercalators12,13 or, contain radiosensitizers as ligands14 for use in radiation therapy and phosphono carboxylates15 as co-ligands in the hope of obtaining some sort of synergistic effect.

     
  3. (3)

    They contain more than one platinum atom16.

     

Keywords

Testicular Cancer Antitumor Drug Platinum Complex Platinum Compound Toxic Side Effect 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    B. Rosenberg, L. Van Camp and T. Krigas, Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode, Nature, 205:698 (1965).PubMedCrossRefGoogle Scholar
  2. 2.
    B. Rosenberg, E. Renshaw, L. Van Camp, J. Hartwick and J. Drobnik, Platinum-induced filamentous growth in Escherichia coli, J. Bacteriol., 93:716 (1967).PubMedGoogle Scholar
  3. 3.
    B. Rosenberg, L. Van Camp, E.B. Grimley and A.J. Thomson, The inhibition of growth or cell division in Escherichia coli by different ionic species of platinum(IV) complexes, J. Biol. Chem., 242:1347 (1967).PubMedGoogle Scholar
  4. 4.
    B. Rosenberg, L. Van Camp, J.E. Trosko and V.H. Mansour, Platinum compounds: a new class of potent antitumour agents, Nature, 222:385 (1969).PubMedCrossRefGoogle Scholar
  5. 5.
    B. Rosenberg, In “Nucleic Acid Metal Ion Interactions” (T. G. Spiro, ed.), p. 3, John Wiley & Sons, New York (1980).Google Scholar
  6. 6.
    J. J. Roberts, A.J. Thomson, The mechanism of action of antitumor platinum compounds, Progr. Nucl. Acid Res. Mol. Biol., 22:71 (1979).CrossRefGoogle Scholar
  7. 7.
    C. F.J. Barnard, Platinum anti-cancer agents; twenty years of continuing development, Plat. Met. Rev., 33:162 (1989).Google Scholar
  8. 8.
    C. F.J. Barnard, M.J. Cleare, P.C. Hydes, Chem. Brit., 22:1001 (1986).Google Scholar
  9. 9.
    N. Farrell, D. Kiley, W. Schmidt and M.P. Hacker, Chemical properties and antitumor activity of complexes of platinum containing substituted sulfoxides [PtCl(R′R″SO)(diamine)]NO3. Chirality and leaving-group ability of sulfoxide affecting biological activity, Inorg. Chem., 29:397 (1990).CrossRefGoogle Scholar
  10. 10.
    S. L. 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
  11. 11.
    H. Schönenberger, B. Wappes, M. Jennerwein and M. Berger, Cancer Treat. Rev., 11:125 (1984).PubMedCrossRefGoogle Scholar
  12. 12.
    B. E. Bowler, K.J. Ahmed, W.I. Sundquist, S.L. Hollis, E.E. Whang and S.J. Lippard, Synthesis, characterization and DNA-binding properties of (1,2-diaminocthane)platinum(II) complexes linked to the DNA intercalator acridine orange by trimethylene and hexamethylene chains, J. Am. Chem. Soc. 111:1299 (1989).CrossRefGoogle Scholar
  13. 13.
    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. 110:8559 (1988).CrossRefGoogle Scholar
  14. W.I. Sundquist, D.P. Bancroft and S.J. Lippard, Synthesis, characterization, and biological activity of cis-diammineplatinum(II) complexes of the DNA intercalators g-aminoacridine and chloroquine, J. Am. Chem. Soc. 112:1590 (1990).CrossRefGoogle Scholar
  15. 14.
    N. Farrell and K.A. Skov, Radiosensitizers targeted to DNA using platinum. Synthesis, characterisation, and DNA binding of cis-[PtCl2(NH3)(nitroimidazole)], J. Chem. Soc. Chem. Commun., 1043 (1987).Google Scholar
  16. 15.
    S. L. Hollis, A.V. Miller, A.R. Amundsen, J.E. Schurig and E.W. Stern, Cis-diamineplatinum(II) complexes containing phosphoro carboxylate ligands as antitumor agents, J. Med. Chem., 33:105 (1990).PubMedCrossRefGoogle Scholar
  17. 16.
    N. Farrell, S. de Almeida and K.A. Skov, Bis(platinum) complexes containing two platinum cis-diammine units. Synthesis and initial DNA-binding studies, J. Am. Chem. Soc. 110:5018 (1988).CrossRefGoogle Scholar
  18. N. Farrell and Y. Qu, Chemistry of bis (platinum) complexes. Formation of trans derivatives from tetraamine complexes, Inorg. Chem., 28:3416 (1989).CrossRefGoogle Scholar
  19. F.D. Rochon and P.C. Kong, Iodo-bridged complexes of platinum(II) and synthesis of mixed-amine platinum(II) compounds, Can. J. Chem., 64:1894 (1986).CrossRefGoogle Scholar
  20. 17.
    S. E. Miller and D.A. House, The hydrolysis products of cis-dichlorodiammineplatinum(II). 2. The kinetics of formation and anation of the cis-diamminedi(aqua)platinum(II) cation, Inorg. Chim. Acta, 166:189 (1989).CrossRefGoogle Scholar
  21. S.E. Miller and D.A. House, The hydrolysis products of cis-dichlorodiammineplatinum(II). 3. Hydrolysis kinetics at physiological pH, Inorg. Chim. Acta, 173:53 (1990).CrossRefGoogle Scholar
  22. 18.
    K. W. Lee and D.S. Martin. Jr., Cis-dichlorodiammineplatinum(II). Aquation equilibria and isotopic exchange of chloride ligands with free chloride and tetrachloroplatinate(II), Inorg. Chim. Acta, 17:105 (1976).CrossRefGoogle Scholar
  23. 19.
    M. C. Lim and R.B. Martin, The nature of cis-amine Pt(II) and antitumor cis-amine Pt(II) complexes in aqueous solutions, J. Inorg. Nucl. Chem., 38:1911 (1976).CrossRefGoogle Scholar
  24. 20.
    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. 112:6860 (1990).CrossRefGoogle Scholar
  25. 21.
    J. Reedijk, The mechanism of action of platinum anti-tumor drugs, Pure & Appl. Chem., 59:181 (1987).CrossRefGoogle Scholar
  26. A. Pasini and F. Zunino, New cisplatin analogues — On the way to better antitumor agents, Angew. Chem., 26:615 (1987).CrossRefGoogle Scholar
  27. J. Reedijk, A.M.J. Fichtinger-Schepman, A.T. van Oosterom and P. van de Putte, Platinum Amine Coordination Compounds as Anti-Tumor Drugs. Molecular Aspects of the Mechanism of Action, Struct. Bonding, 67:53 (1987).CrossRefGoogle Scholar
  28. S.E. Sherman and S.J. Lippard, Structural aspects of platinum anticancer drug interactions with DNA, Chem. Rev., 87:1153 (1987).CrossRefGoogle Scholar
  29. N. Farrell, In “Transition Metal Complexes as Drugs and Chemotherapeutic agents”, Kluwer Academic Publishers, Dordrecht (1989).CrossRefGoogle Scholar
  30. W.I. Sundquist and S.J. Lippard, The coordination chemistry of platinum anticancer drugs and related compounds with DNA, Coord. Chem. Rev., 100:293 (1990).CrossRefGoogle Scholar
  31. 22.
    J. C. Chottard, J.P. Girault, G. Chottard, J.Y. Lallemand and D. Mansuy, Interaction of cis-[Pt(NH3)2(H2O)2] (NO3)2 with ribose dinucleoside monophosphates, J. Am. Chem. Soc., 102:5566 (1980).CrossRefGoogle Scholar
  32. F.J. Dijt, J.C. Chottard, J.P. Girault and J. Reedijk, Formation and structure of reaction products of cis-PtCl2(NH3)2 with d(ApG) and/or d(GpA) in di-, tri-and penta-nucleotides, Eur. J. Biochem., 179:333 (1989).CrossRefGoogle Scholar
  33. J.P. Caradonna and S.J. Lippard, Synthesis and characterization of [d(ApGpGpCpCpT)]2 and its adducts with the anticancer drug cis-diamminedichloroplatinum(II), Inorg. Chem., 27:1454 (1988).CrossRefGoogle Scholar
  34. M.D. Reily and L.G. Marzilli, Anti-cancer Pt drug adducts with AMP: novel direct 1H and 195Pt NMR evidence for slowly interconverting “head-to-tail” rotamers. Potential role of amine ligand bulk and NH groups in guanine selectivity and anti-cancer activity, J. Am. Chem. Soc., 108:6785 (1986).CrossRefGoogle Scholar
  35. C. Spellmeyer-Fouts, L.G. Marzilli, R.A. Byrd, M.F. Summers, G. Zon and K. Shinozuka, HMQC and 1H and 31P NMR studies of platinum amine adducts of tetradeoxyribonucleotides. Relationship between 31P shift and potential hydrogen-bonding interactions in pGpG moieties cross-linked by platinum, Inorg. Chem., 27:366 (1988).CrossRefGoogle Scholar
  36. 23.
    W. M. Scovell and V.J. Capponi, Cis-diamminedichloroplatinum(II) modified DNA stimulates far greater levels of S-1 nuclease sensitive regions than does the modification produced by the trans-isomer, Biochem. Biophys. Res. Commun., 107:1138 (1982).PubMedCrossRefGoogle Scholar
  37. 24.
    A. M. Fichtinger-Schepman, J.L. van der Veer, J.H.J. den Hartog, P.H.M. Lohman and J. Reedijk, Adducts of the Antitumor Drug cis-Diamminedichloroplatinum(II) with DNA: Formation, Identification and Quantitation, Biochemistry, 24:707 (1985).PubMedCrossRefGoogle Scholar
  38. 25.
    S. Sherman, D. Gibson, A.H.J. Wang and S.J. Lippard, X-ray structure of the major adduct of the anticancer drug cisplatin with DNA: cis-[Pt(NH3)2d(pGpG)], Science, 230:412 (1985).PubMedCrossRefGoogle Scholar
  39. S. 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
  40. 26.
    M. Coll, S. Sherman, D. Gibson, S.J. Lippard and A.H.J. Wang, Molecular structure of the complex formed between the anticancer drug cisplatin and d(pGpG): C222, crystal form, J. Biomol. Struct. & Dynam., 8:315 (1990).CrossRefGoogle Scholar
  41. 27.
    G. Admiraal, J. van der Veer, R.A.G. de van der Graaff, J.H.J. den Hartog and J. Reedijk, Intrastrand Bis(guanine) Chelation of d(CpGpG) to cis-Platinum: An X-ray Single-Crystal Structure Analysis, J. Am. Chem. Soc. 109:592 (1987).CrossRefGoogle Scholar
  42. 28.
    C. J. van Garderen, L.P.A. van Houte, H. van den Eist, J.H. van Boom and J. Reedijk, A Double-Stranded DNA Fragment Shows a Significant Decrease in Double-Helix Stability After Binding of Monofunctional Platinum Amine Compounds, J. Am. Chem. Soc. 111:4123 (1989).CrossRefGoogle Scholar
  43. C.J. van Garderen, C. Altona and J. Reedijk, Inorg. Chem., 29:1481 (1990).CrossRefGoogle Scholar
  44. 29.
    G. Admiraal, F.J. Dijt, C.J. van Garderen, R.A.G. de Graaff and J. Reedijk, J. Am. Chem. Soc., manuscript in preparation.Google Scholar
  45. 30.
    D. L. Bodenner, P.C. Dedon, P.C. Keng and R.F. Borch, Effect of diethyldithiocarbamate on cis-diamminedichloroplatinum(II)-induced cytotoxicity, DNA cross-linking, and γ-glutamyl transpeptidase inhibition, Cancer Res., 46:2745 (1986).PubMedGoogle Scholar
  46. 31.
    A. F. LeRoy and W.C. Thompson, J. N’atl. Cancer Inst., 81:427 (1989).CrossRefGoogle Scholar
  47. 32.
    B. J. Corden, Reaction of platinum(II) antitumor agents with sulfhydral compounds and the implications for nephrotoxicity, Inorg. Chim. Acta, 137:125 (1987).CrossRefGoogle Scholar
  48. 33.
    J. D. Otvos, D.H. Petering and C.F. Shaw, Structure-reactivity relationships of metallothionein, a unique metal-binding protein, Comm. Inorg. Chem., 9:1 (1989).CrossRefGoogle Scholar
  49. 34.
    M. I. Djuran, E.L.M. Lempers and J. Reedijk, Reactivity of Chloro and Aquadiethylenetriamineplatinum(II) Ions with Glutathione, S-Methyl Glutathione and Guanosine 5′-Monophosphate in Relation to the Antitumor Activity and Toxicity of Platinum Complexes, Inorg. Chem., in press (1991).Google Scholar
  50. 35.
    E. L. Lempers, K. Inagaki and J. Reedijk, Reactions of [PtCl(dien)]Cl with Glutathione, Oxidized Glutathione and S-Methyl Glutathione. Formation of an S-bridged Dinuclear Unit, Inorg. Chim. Acta, 152:201 (1988).CrossRefGoogle Scholar
  51. E.L.M. Lempers and J. Reedijk, Reversibility of Binding of Cisplatin-Methionine in Proteins by Diethyldithiocarbamate or Thiourea: A Study with Model Adducts, Inorg. Chem., 29:217 (1990).CrossRefGoogle Scholar
  52. 36.
    E. L. Lempers and J. Reedijk, Characterization of Products from [PtCl(dien)]Cl and S-Adenosyl-L-homocysteine. Evidence for a pH-Dependent Migration of the Platinum Moiety from the Sulfur Atom to the Amine Group and Vice Versa, Inorg. Chem., 29:1880 (1990).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Jan Reedijk
    • 1
  1. 1.Gorlaeus LaboratoriesLeiden UniversityThe Netherlands

Personalised recommendations