The effects of sulfur-containing compounds and gemcitabine on the binding of cisplatin to plasma proteins and DNA determined by inductively coupled plasma mass spectrometry and high performance liquid chromatography-inductively coupled plasma mass spectrometry.
The aim of this study was to investigate the effects of sodium thiosulfate (STS), glutathione (GSH), acetylcysteine (AC), and gemcitabine on the platinum-protein (Pt-protein) and platinum-DNA (Pt-DNA) binding of cisplatin in whole blood. This was done to obtain more insight into the platinum (Pt) binding in whole blood and the effects of modulators on this process. STS, GSH, AC, and gemcitabine were added before and after the incubation of whole blood with cisplatin. Pt levels in plasma and plasma ultrafiltrate and the Pt that is bound to DNA in peripheral blood mononuclear cells were determined using inductively coupled plasma mass spectrometry. Additionally, information on the major Pt-DNA adducts was obtained by separation of the Pt-DNA adducts by high performance liquid chromatography with off-line inductively coupled plasma mass spectrometry detection. Results showed that the reactive Pt levels in whole blood are reduced by STS, GSH, and AC. This reduction was demonstrated by a reduced Pt-protein and Pt-DNA binding in the presence of sulfur compounds. Furthermore, STS and AC seemed to be able to release Pt from proteins. The compounds could hardly release Pt from the DNA. Gemcitabine slightly inhibited Pt-DNA binding and did not alter Pt-protein binding. The type of Pt-DNA adducts found were not altered in the presence of the modulators. In conclusion, the results of this study illustrate that STS, GSH, and AC affect Pt binding in whole blood, which suggests that these compounds could affect Pt binding in patients. By interfering with Pt-DNA and Pt-protein binding, the compounds could influence side effects and cytotoxicity.
Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Louwesweg 6, The Netherlands. Elke.Brouwers@slz.nl
Elke E M
EE
Brouwers
Alwin D R
AD
Huitema
Jan H M
JH
Schellens
Jos H
JH
Beijnen
D000111:Acetylcysteine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D013058:Mass Spectrometry; D011485:Protein Binding; D013885:Thiosulfates / Q000494:pharmacology*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D001798:Blood Proteins; D013885:Thiosulfates; D003841:Deoxycytidine; D004247:DNA; D005978:Glutathione; C017717:sodium thiosulfate; D002945:Cisplatin; D000111:Acetylcysteine; D000093542:Gemcitabine