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Issue 10, 2011
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Speciation of oxaliplatin adducts with DNAnucleotides

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Abstract

This paper describes a set of fast and selective high performance liquid chromatography (HPLC) methods coupled to electro-spray ionisation linear ion trap mass spectrometry (ESI–MS), sector-field inductively coupled plasma mass spectrometry (SF-ICP-MS) and UV detection for in vitro studies of the bifunctional adducts of oxaliplatin with mono-nucleotides, di-nucleotides and cellular DNA. The stationary phases and the optimised conditions used for each separation are discussed. Interaction of oxaliplatin with A and G mono-nucleotides resulted in the formation of five bifunctional platinum diaminocyclohexane (DACHPt) adducts. These were two isomers of the A-DACHPt-A and A-DACHPt-G adducts, and one G-DACHPt-G adduct, as confirmed by MS/MS spectra obtained by collision induced dissociation. These adducts were also characterised by UV absorption data and SF-ICP-MS elemental 195Pt and 31P signals. Further, interaction of oxaliplatin with AG and GG di-nucleotides resulted in the formation of three adducts: DACHPt-GG and two isomers of the DACHPt-AG adduct, as confirmed by ESI-MS and the complementary data obtained by UV and SF-ICP-MS. Finally, a very sensitive LC-ICP-MS method for the quantification of oxaliplatin GG intra-strand adducts (DACHPt-GG) was developed and used for monitoring the in vitro formation and repair of these adducts in human colorectal cancer cells. The method detection limit was 0.14 ppb Pt which was equivalent to 0.22 Pt adduct per 106 nucleotides based on a 10 μg DNA sample. This detection limit makes this method suitable for in vivo assessment of DACHPt-GG adducts in patients undergoing oxaliplatin chemotherapy.

Graphical abstract: Speciation of oxaliplatin adducts with DNA nucleotides

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Publication details

The article was received on 12 Apr 2011, accepted on 19 Jul 2011 and first published on 22 Aug 2011


Article type: Paper
DOI: 10.1039/C1MT00041A
Metallomics, 2011,3, 991-1000

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    Speciation of oxaliplatin adducts with DNA nucleotides

    A. Zayed, G. D. D. Jones, H. J. Reid, T. Shoeib, S. E. Taylor, A. L. Thomas, J. P. Wood and B. L. Sharp, Metallomics, 2011, 3, 991
    DOI: 10.1039/C1MT00041A

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