Skip to main content
SpringerLink
Log in

Toxicity of Metal Complexes with Radiosensitizing Properties

  • Chapter
Selective Activation of Drugs by Redox Processes

Part of the book series: NATO ASI Series ((NSSA,volume 198))

Abstract

Development of radiosensitizers has focused on organic compounds, for the most part, nitroimidazoles. The relationship of the efficiency of sensitization to E 1–2 was noted for nitroimidazoles during structure/activity studies1. However, changing the reduction potential to increase sensitizing efficiency is impractical beyond a certain point due to the accompanying toxicity2. This toxicity, which is more pronounced in hypoxic cells3, is due to metabolic reduction of the nitroaromatic group (e.g. Rauth4). Considerable attention has been given to both exploiting this selective toxicity as described in this volume (chemosensitization, hypoxic cytotoxins and markers for hypoxia) and to minimizing the toxicity which results in side-effects. Complexes of certain metals may offer some advantages because of their redox properties, thiol reactivity and DNA binding properties, as previously summarized5,6. DNA binding may itself lead to an interaction with ionizing radiation, and DNA binding metals may be used to target nitroaromatics to DNA. Alternatively, certain transition metals (e.g. Fe, Co, Ni, Cu) surrounded by suitable ligands may have reduction potentials in the appropriate range.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. G.E. Adams, I.R. Flockhart, C.E. Smithen, I.J. Stratford, P. Wardman, and M.E. Watts, Electron-affinic sensitization. VII. A correlation between structures, one-electron reduction potentials, and efficiencies of nitroiraidazoles as hypoxic cell radiosensitizers, Radiat. Res. 67:9 (1976).

    Article  PubMed  CAS  Google Scholar 

  2. G.E. Adams, E.D. Clarke, P. Gray, R.S. Jacobs, I.J. Stratford, P. Wardman, M.E. Watts, J. Parrick, R.G. Wallace, and C.E. Smithen, Structure-activity relationships in the development of hypoxic cell radiosensitizers. II. Cytotoxicity and therapeutic ratio, Int. J. Radiat. Biol. 35:151 (1979).

    Article  CAS  Google Scholar 

  3. B.A. Moore, B. Palcic, and L.D. Skarsgard, Radiosensitizing and toxic effects of the 2-nitroimidazole Ro-07-0582 in hypoxic mammalian cells, Radiat. Res. 67:459 (1976).

    Article  PubMed  CAS  Google Scholar 

  4. A.M. Rauth, Pharmacology and toxicology of sensitizers: mechanism studies, Int. J. Radiat. Oncol. Biol. Phys. 10:1293 (1984).

    Article  PubMed  CAS  Google Scholar 

  5. K.A. Skov, Modification of radiation response by metal complexes: A review with emphasis on non-platinum studies, Radiat. Res. 112:217 (1987).

    Article  PubMed  CAS  Google Scholar 

  6. N.P. Farrell, Transition metal complexes as drugs and chemotherapeutic agents, in: “Catalysis by metal complexes”, B.R. James and R. Ugo, eds., Reidel-Kluwer, Dordrecht (1989).

    Google Scholar 

  7. M.E. Varnes and J.E. Biaglow, Interactions of the carcinogen 4-nitroquinoline 1-oxide with the non-protein thiols of mammalian cells, Cancer Res. 39:2960 (1979).

    PubMed  CAS  Google Scholar 

  8. K.A. Skov, H. Adomat, D.C. Konway, and N.P. Farrell, Assessment of DNA binding of platinum-radiosensitizer complexes by inhibition of restriction enzymes, Chem. Biol. Interact. 62:117 (1987).

    Article  PubMed  CAS  Google Scholar 

  9. L. Dewit, Combined treatment of radiation and cisdiamminedichloroplatinum(II): A review of experimental and clinical data, Int. J. Radiat. Oncol. Biol. Phys. 13:403 (1987).

    Article  PubMed  CAS  Google Scholar 

  10. E.B. Douple and R.C. Richmond, A review of interactions between platinum co-ordination complexes and ionizing radiation: Implications for cancer therapy, in: “Cis platin: Current status and new developments”, A.W. Prestayko, S.F. Crooke and S.K. Carter, eds., Academic Press, New York (1980).

    Google Scholar 

  11. J.A. O’Hara, E.B. Douple, and R.C. Richmond, Enhancement of radiation-induced cell kill by platinum complexes (carboplatin and iproplatin) in V79 cells, Int. J. Radiat. Oncol. Biol. Phys. 12:1419 (1986).

    Article  PubMed  Google Scholar 

  12. R. Chibber, I.J. Stratford, P. O’Neill, P.W. Sheldon, I. Ahmed, and B. Lee, The interaction between radiation and complexes of cis-Pt(II) and Rh(II): studies at the molecular and cellular level. Int. J. Radiat. Biol. 48:513 (1985).

    Article  CAS  Google Scholar 

  13. J. Butler, B.M. Hoey, and A.J. Swallow, The radiation chemistry of some platinum-containing radiosensitizers and related compounds, Radiat. Res. 102:1 (1985).

    Article  PubMed  CAS  Google Scholar 

  14. I.J. Stratford, C. Williamson, and G.E. Adams, Combination studies with misonidazole and a cis-platinum complex: cytotoxicity and radiosensitization in vitro, Br. J. Cancer. 41:517 (1980).

    Article  PubMed  CAS  Google Scholar 

  15. K.A. Skov, M. Korbelik, and B. Palcic, The interaction of trans-Diamminedichloroplatinum (II) with low radiation doses in mammalian cells, Int. J. Radiat. Oncol. Biol. Phys. 16:1281 (1989).

    Article  PubMed  CAS  Google Scholar 

  16. M. Korbelik, and K.A. Skov, Inactivation of hypoxic cells by cisplatin and radiation at clinically relevant doses, Radiat. Res. 119:145 (1989).

    Article  PubMed  CAS  Google Scholar 

  17. J.E. Melvik, and E.O. Pettersen, Oxygen- and temperature- dependent cytotoxic and radiosensitizing effects of cis-dichlorodiammineplatinum(II) on human NHIK 3025 cells in vitro, Radiat. Res. 114:489 (1988).

    Article  PubMed  CAS  Google Scholar 

  18. B.A. Teicher, J.S. Lazo, and A.C. Sartorelli, Classification of antineoplastic agents by their selective toxicities towards oxygenated and hypoxic tumor cells, Cancer Res. 41:73 (1981).

    PubMed  CAS  Google Scholar 

  19. K.A. Skov, N.P. Farrell, and H. Adomat, Platinum complexes with one radiosensitizing ligand [PtCl2(NH3)(sensitizer)], Radiat. Res. 112:273 (1987).

    Article  PubMed  CAS  Google Scholar 

  20. N.P. Farrell, T. Gomes De Carneiro, F.W.B. Einstein, T. Jones, and K.A. Skov, Synthesis and characterization of nitroimidazole complexes of platinum and palladium and the crystal and molecular structure of trans-dichlorobis(misonidazole)-platinum(II), Inorg. Chim. Acta. 92:61 (1984).

    Article  CAS  Google Scholar 

  21. E. Smith, O.C.A. Scott, A.H.W. Nias, A.P. Brock, Letter to the Editor, Br. J. Radiol. 60:601 (1987).

    Article  PubMed  CAS  Google Scholar 

  22. K.A. Skov and N.P. Farrell, Binding mode of 2-amino-5-nitrothiazole (ANT) in platinum complexes trans-[PtCl2(ANT)2] affects DNA binding, toxicity and radiosensitizing ability, Int. J. Radiat. Biol. 52:289 (1987).

    Article  CAS  Google Scholar 

  23. B.A. Teicher, S. Rockwell, and J.B. Lee, Radiosensitization of EMT6 cells by four platinum complexes, Int. J. Radiat. Oncol. Biol. Phys. 11:937 (1984).

    Article  Google Scholar 

  24. K.A. Skov and N.P. Farrell, Radiosensitization by complexes of 4(5) nitroimidazole, Int. J. Radiat. Biol. (In Press, 1990).

    Google Scholar 

  25. K.A. Skov, H. Adomat, D.J. Chaplin, and N.P. Farrell, Toxicity of [PtCl2(NH3)NO2Im] in hypoxia (Abstract 1850). Proc. 80th Ann. Mtg. American Assoc. Cancer Res. 30:465; and Anti-Cancer Drug Design 5 (In press, 1990).

    Google Scholar 

  26. R. Chibber, I.J. Stratford, I. Ahmed, A.B. Robbins, D. Goodgame, and B. Lee, Radiosensitization of mammalian cells by transition metal complexes containing nitroimidazole ligands, Int. J. Radiat. Oncol. Biol. Phys. 10:1213 (1984).

    Article  PubMed  CAS  Google Scholar 

  27. J.R. Bales, C.J. Coulson, D.W. Gilmour, M.A. Maxid, S. Neidle, R. Kuroda, B.J. Peart, C.A. Ramsden, and P.J. Sadler, The preparation and isoraerization of platinum metronidazole complexes, J. Chem. Soc. Commun. 432 (1983).

    Google Scholar 

  28. N.P. Farrell and K.A. Skov, Radiosensitizers targetted to DNA using platinum, Synthesis, characterization an DNA binding of cis-[PtCl2(NH3)(radiosensitizer)], J. Chem. Soc. Chem. Commun. 1043 (1987).

    Google Scholar 

  29. P.K.L. Chan, PhD. Thesis, Ruthenium nitroimidazole complexes as radiosensitizers, University of British Columbia, Vancouver, (1988).

    Google Scholar 

  30. P.K.L. Chan, K.A. Skov, N.P. Farrell, and B.R. James, A new ruthenium radiosensitizer: RuCl2(DMSO)2(4-nitroimidazole)2. Int. J. Radiat. Oncol. Biol. Phys. 12:1059 (1986).

    Article  PubMed  CAS  Google Scholar 

  31. P.K.L. Chan, P.K.H. Chan, D.C. Frost, B.R. James, and K.A. Skov, Ruthenium (II) complexes of 4-nitroimidazoles: their characterization solution chemistry and radiosensitizing activity, Can. J. Chem. 66:117 (1988).

    CAS  Google Scholar 

  32. P.K.L. Chan, B.R. James, D.C. Frost, P.K.H. Chan, H-L Hu, and K.A. Skov, Effects of halide (X) and sulphoxide (R2SO) replacement within the ruthenium (II) nitroimidazole complexes, RuX2(R2SO)m (nitroimidazole)n, m=1–3, n=1 or 2: their characterization, solution chemistry, radiosensitizing activity, and related properties, Can. J. Chem. 67:508 (1989).

    Article  CAS  Google Scholar 

  33. A.M. Joy, D.M.L. Goodgame, and I.J. Stratford, High efficiency of ferricenium salts as radiosensitizers of V79 cells in vitro and the KHT tumor in vivo, Int. J. Radiat. Oncol. Biol. Phys. 16:1053 (1989).

    Article  PubMed  CAS  Google Scholar 

  34. B.A. Teicher, J.L. Jacobs, K.N.S. Cathcart, M.J. Abrams, J.F. Vollano, and D.H. Picker, Some complexes of cobalt(III) and iron(III) are radiosensitizers of hypoxic EMT6 cells, Radiat. Res. 109:36 (1987).

    Article  PubMed  CAS  Google Scholar 

  35. J.A. O’Hara, E.B. Douple, M.J. Abrams, D.J. Picker, C.M. Giandomenico, and J.F. Vollano, Potentiation of radiation-induced cell kill by synthetic metalloporphyrins, Int. J. Radiat. Oncol. Biol. Phys. 16:1049, (1989).

    Article  PubMed  Google Scholar 

  36. K.A. Skov, H. Adomat, and N.P. Farrell, Effects of nickel-lapachol in hypoxic cells, in: “Platinum and other coordination compounds in cancer chemotherapy”, M. Nicolini, ed., Martinus-Nijhoff, Boston (1988).

    Google Scholar 

  37. B. Palcic, and L.D. Skarsgard, Cytotoxicity of misonidazole and DNA damage in hypoxic mammalian cells, Br. J. Cancer, 37:54 (1978).

    CAS  Google Scholar 

  38. I.P. Hesslewood, W.A. Cramp, D.C.H. McBrien, P. Williamson, and K.A.K. Lott, Copper as a hypoxic cell sensitizer of mammalian cells, Br. J. Cancer, 37:95 (1978).

    CAS  Google Scholar 

  39. D.J. Chaplin, Hydralazine induced tumour hypoxia: a potential target for cancer chemotherapy, JNCI. 81:618 (1989).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Biophysics Unit, B.C. Cancer Research Centre, 601 West 10th Avenue, Vancouver, B.C., V5Z 1L3, Canada

    Kirsten A. Skov

Authors
  1. Kirsten A. Skov
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. MRC Radiobiology Unit, Didcot, Chilton, Oxon., OX11 ORD, UK

    G. E. Adams  & E. M. Fielden  & 

  2. Facoltà di Farmacia, Istituto di Scienze Chimiche, Università Degli Studi di Bologna, 40127, Bologna, Via S. Donato, 15, Italy

    A. Breccia

  3. CRC Gray Laboratory, Mount Vernon Hospital, Northwood, Middlesex, HA6 2JR, UK

    P. Wardman

Rights and permissions

Reprints and permissions

Copyright information

© 1990 Springer Science+Business Media New York

About this chapter

Cite this chapter

Skov, K.A. (1990). Toxicity of Metal Complexes with Radiosensitizing Properties. In: Adams, G.E., Breccia, A., Fielden, E.M., Wardman, P. (eds) Selective Activation of Drugs by Redox Processes. NATO ASI Series, vol 198. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3768-7_24

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-3768-7_24

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6679-9

  • Online ISBN: 978-1-4615-3768-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation