Ionenfallen-Massenspektrometrie von Cisplatin-DNA-Addukten

Timo Hagemeister

ISBN 978-3-8325-0117-4
175 pages, year of publication: 2003
price: 40.50 €

cis-Diamminedichloroplatin(II) is a chemotherapeutic in wide spread use. The revelation of the detailed mechanism of action of cisplatin is of crucial importance to improve the characteristics of the cytostatic drug on the basis of interaction with human bio molecules. An important step in the cytotoxic reaction is, as it is well known today, the formation of adducts with the nucleobases of the DNA.

In this work an ion trap mass spectrometer with electrospray ionisation was employed to detect and elucidate the structure of the partially low concentrated cisplatin-DNA-adducts. After a preceding chromatographic separation step which was coupled to the ESI-sprayer, the platinum binding positions to the enzymatically generated smallest possible cisplatin-complexes (adducts to dinucleotides) as well as the sequence of nucleotides directly adjoining the lesions were determined by fragmentation. The existence of several formerly unknown crosslinks (1,2-intrastrand-GT-, 1,2-intrastrand-AA-, 1,3-intrastrand-AG- and 1,2-interstrand-AG-adducts) as well as a distinct but not exclusive sequence specifity for thymidine could be shown.

Additionally experiments to investigate the gas phase behaviour of platinum-complexes in the ion trap were performed using cisplatin-adducts to selected dinucleosidemonophosphates. It could be shown that the complexes are highly reactive, undergoing numerous intramolecular reactions after the unblocking of a coordination site at the platinum center.