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

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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.

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.

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Abbreviations

Dach:

Diaminocyclohexane

CID:

Collision-induced dissociation

ESI-MS:

Electrospray ionisation–mass spectrometry

GMP:

Guanine monophosphate

A:

Adenine

C:

Cytosine

G:

Guanine

T:

Thymine

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Authors and Affiliations

  1. Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK

    Samantha L. Kerr, Tamer Shoeib & Barry L. Sharp

  2. Department of Chemistry, British University in Egypt, El Sherouk, Cairo, 11837, Egypt

    Tamer Shoeib

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  1. Samantha L. Kerr
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  2. Tamer Shoeib
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  3. Barry L. Sharp
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Correspondence to Barry L. Sharp.

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Kerr, S.L., Shoeib, T. & Sharp, B.L. A study of oxaliplatin–nucleobase interactions using ion trap electrospray mass spectrometry. Anal Bioanal Chem 391, 2339–2348 (2008). https://doi.org/10.1007/s00216-008-2128-3

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  • DOI: https://doi.org/10.1007/s00216-008-2128-3

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