The reversal of cisplatin-protein interactions by the modulating agent WR2721 and its metabolites WR1065 and WR33278

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 Ptmethionine-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.