title: The reversal of cisplatin-protein interactions by the modulating agent WR2721 and its metabolites WR1065 and WR33278.
abstract: The reversibility of cisplatin-protein interactions by the modulating agent WR2721, its active thiol-metabolite WR1065, and the symmetrical disulfide WR33278 was studied using the model compounds (Pt(diethylenetriammine) monofunctionally bound to the sulfur in glutathione (Pt(dien)SG) and Pt(diethylenetriammine) monofunctionally bound to the sulfur in S-methylglutathione (Pt(dien)SMeG). Both model compounds could be quantified by high-performance liquid chromatography (HPLC) with UV detection. The Pt-cysteine-like bond in Pt(dien)SG could not be reversed by any of the WR compounds or by the strong nucleophiles thiosulfate (TS) and diethyldithiocarbamate (DDTC). However, the Pt-methionine-like bond in Pt(dien)SMeG could be reversed by WR1065, although the reversal was slow (k2 = 0.142 M-1 s-1) as compared with that obtained using the modulating agents TS (k2 = 10.1 M-1 s-1) and DDTC (k2 = 3.66 M-1 s-1). WR2721 was hardly able to reverse the Pt-S bond in Pt(dien)SMeG (k2 = 0.00529 M-1 s-1), and WR33278 showed no capacity to do so. The activity of cis-diamminedichloroplatinum(II) (CDDP)-inactivated fumarase was not appreciably restored by any of the WR compounds (16%, 7.7%, and 0 for 20 mM WR1065, WR2721, and WR33278, respectively) in contrast to the strong nucleophile DDTC (61% for 2 mM DDTC). These in vitro studies provide information at the molecular level that may explain why WR2721, in contrast to DDTC, does not provide protection against cisplatin-induced nephrotoxicity when it is given after platinum-containing chemotherapy. The results support the present clinical use of WR2721 prior to the administration of platinum compounds.
authors.affiliation: Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Treskes
authors.forename: U
authors.initials: U
authors.lastname: Holwerda
authors.forename: L G
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: W J
authors.initials: WJ
authors.lastname: van der Vijgh
mesh_terms: D004999:Amifostine / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D002945:Cisplatin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D004347:Drug Interactions; D004355:Drug Stability; D005649:Fumarate Hydratase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D007700:Kinetics; D008624:Mercaptoethylamines / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C074168:chlorodiethylenetriamine platinum(II)-S-methyl-glutathione complex; C074167:chlorodiethylenetriamine platinum(II)-glutathione complex; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004050:Ditiocarb; D005649:Fumarate Hydratase; D005978:Glutathione; D004999:Amifostine; D002945:Cisplatin; C045611:WR 33278