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Analytical and Bioanalytical Chemistry

, Volume 391, Issue 6, pp 2339–2348 | Cite as

A study of oxaliplatin–nucleobase interactions using ion trap electrospray mass spectrometry

  • Samantha L. Kerr
  • Tamer Shoeib
  • Barry L. SharpEmail author
Original Paper

Abstract

Oxaliplatin is an important anti-cancer drug that has been approved for the treatment of colorectal cancer. It is known that oxaliplatin, like other Pt-based drugs, interacts with DNA to form cytotoxic Pt-DNA adducts that disrupt important biological processes such as DNA replication and protein synthesis. Linear ion trap electrospray ionisation mass spectrometry (ESI-MS) was employed to study the interaction of oxaliplatin with DNA nucleobases. It was shown that oxaliplatin formed adducts with all four DNA nucleobases when present individually and in combination in solution. Multiple-stage tandem mass spectrometry (MSn) enabled the fragmentation pathways of each adduct to be established. In addition, proposed structures for each product ion were obtained from the MS data. When all four bases were present together with the drug at near-equal molar concentrations, adducts containing predominantly adenine and guanine were formed, confirming that the drug preferentially binds to these nucleobases. A large molar excess of drug was required to ensure the formation of cytosine and thymine adducts in the presence of adenine and guanine. Even with a large excess of oxaliplatin, only mono-adducts of these nucleobases were observed when all four nucleobases were present.

Figure

Schematic of a linear ion trap mass spectrometer being used to isolate the diadduct of guanine with oxaliplatin showing the characteristic isotope pattern due to 194Pt, 195Pt and 196Pt.

Keywords

Oxaliplatin DNA Nucleobase interactions Ion trap ESI-MS Adduct formation Pharmaceuticals 

Abbreviations

Dach

Diaminocyclohexane

CID

Collision-induced dissociation

ESI-MS

Electrospray ionisation–mass spectrometry

GMP

Guanine monophosphate

A

Adenine

C

Cytosine

G

Guanine

T

Thymine

References

  1. 1.
    Bell DN, Liu JJ, Tingle MD, McKeage MJ (2006) J Chromatogr B 837:29–34CrossRefGoogle Scholar
  2. 2.
    Reedijk J (2003) Proc Natl Acad Sci USA 100:3611–3616CrossRefGoogle Scholar
  3. 3.
    Ta LE, Espeset L, Podratz J, Windebank AJ (2006) Neurotoxicology 27:992–1002CrossRefGoogle Scholar
  4. 4.
    Jamieson ER, Lippard SJ (1999) Chem Rev 99:2467–2498CrossRefGoogle Scholar
  5. 5.
    Arnould S, Hennebelle I, Canal P, Bugat R, Guichard S (2003) Eur J Cancer 39:112–119CrossRefGoogle Scholar
  6. 6.
    Almeida GM, Duarte TL, Steward WP, Jones GDD (2006) DNA Repair 5:219–225CrossRefGoogle Scholar
  7. 7.
    Chaney SG, Campbell SL, Temple B, Bassett E, Wu Y, Faldu M (2004) J Inorg Biochem 98:1551–1559CrossRefGoogle Scholar
  8. 8.
    Mandal R, Sawyer MB, Li X-F (2006) Rapid Commun Mass Spectrom 20:2533–2538CrossRefGoogle Scholar
  9. 9.
    Woynarowski JM, Chapman WG, Napier C, Herzig MCS, Juniewicz P (1998) Mol Pharmacol 54:770–777Google Scholar
  10. 10.
    Rodger A, Patel KK, Sanders KJ, Datt M, Sacht C, Hannon MJ (2002) J Chem Soc Dalton Trans 3656–3663Google Scholar
  11. 11.
    Garcia Sar D, Montes-Bayón M, Blanco Gonzalez E, Sanz-Medel A (2006) J Anal Atom Spectrom 21:861–868CrossRefGoogle Scholar
  12. 12.
    Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK (2006) Chem Rev 106:2224–2248CrossRefGoogle Scholar
  13. 13.
    Pluim D, Maliepaard M, Van Waardenburg RCAM, Beijnen JH, Schellens JHM (1999) Anal Biochem 275:30–38CrossRefGoogle Scholar
  14. 14.
    Meczes EL, Azim-Araghi A, Ottley CJ, Pearson DG, Tilby MJ (2005) Biochem Pharmacol 70:1717–1725CrossRefGoogle Scholar
  15. 15.
    Küng A, Strickmann DB, Galanski M, Keppler BK (2001) J Inorg Biochem 86:691–698CrossRefGoogle Scholar
  16. 16.
    Luo FR, Yen T-Y, Wyrick SD, Chaney SG (1999) J Chromatogr B 724B:345–356Google Scholar
  17. 17.
    Spingler B, Whittington DA, Lippard SJ (2001) Inorg Chem 40:5596–5602CrossRefGoogle Scholar
  18. 18.
    Wu YB, Pradhan P, Havener J, Cambell S, Chaney SG (2004) Abs Pap Am Chem Soc 228:U178Google Scholar
  19. 19.
    Yan X, Watson J, Shing Ho P, Deinzer ML (2004) Mol Cell Proteomics 3:10–23Google Scholar
  20. 20.
    Raji MA, Frycak P, Beall M, Sakrout M, Ahn J-M, Bao YP, Armstrong DW, Schug KA (2007) Int J Mass Spectrom 262:232–240CrossRefGoogle Scholar
  21. 21.
    Iijima H, Patrzyc HB, Dawidzik JB, Budzinski EE, Cheng H-C, Freund HG, Box HC (2004) Anal Biochem 333:65–71CrossRefGoogle Scholar
  22. 22.
    Iannitti-Tito P, Weimann A, Wickham G, Sheil MM (2000) Analyst 125:627–634CrossRefGoogle Scholar
  23. 23.
    Le Pla RC, Ritchie KJ, Henderson CJ, Wolf CR, Harrington CF, Farmer PB (2007) Chem Res Toxicol 20:1177–1182CrossRefGoogle Scholar
  24. 24.
    Shriver DF, Atkins PW, Langford CH (1994) Inorganic chemistry. Oxford University Press, OxfordGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Samantha L. Kerr
    • 1
  • Tamer Shoeib
    • 1
    • 2
  • Barry L. Sharp
    • 1
    Email author
  1. 1.Department of ChemistryLoughborough UniversityLoughboroughUK
  2. 2.Department of ChemistryBritish University in EgyptCairoEgypt

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