Fast atom bombardment and high performance tandem mass spectrometry of platinum(II) oligodeoxyribonucleotide fragments

Abstract

The antitumor drug cisplatin [ cis-diamminedichloroplatinum(II), cis-DDP] exerts its biological activity by binding to cellular DNA. In order to evaluate the utility of mass spectrometry as a possible new approach to investigate the number and type of Pt-DNA adducts in both mechanistic and clinical studies, a systematic survey of the fast atom bombardment (FAB) and high performance tandem mass spectrometry (MSMS) spectra of a series of well-defined adducts has been carried out. Included in the set of compounds were adducts between cisplatin or its trans isomer and oligodeoxyribonucleotides containing two to six bases, selected to represent all the known binding modes of cisplatin to DNA, and stable isotope-labeled ( 15N, 195Pt) complexes. In both positive- and negative-ion FAB mass spectra, all compounds yield ions corresponding to the singly-charged intact cluster, and to fragments that arise by loss of one or two ammine groups. The isotope ratio patterns of the clusters indicate that mixed species containing varying numbers of hydrogens are present. MS—MS spectra obtained after high energy (1–7keV) collisionally-induced dissociation (CID) have more extensive fragmentation. Two sets of product ions indicative of the Pt- binding site are consistently present; these correspond to Pt(NH 3) 0–2 (B x or y ) and Pt(NH 3) 0–2 (B x B y ), where B x and B y are the nucleobasis linked to Pt in the adduct. CID mass spectra recorded at 1 keV have additional product ions related to the nucleotide sequence.