Treskes M, Holwerda U, Nijtmans L G, Pinedo H M, van der Vijgh W J
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 1992;29(6):467-70. doi: 10.1007/BF00684849.
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.
使用模型化合物（单官能团结合到谷胱甘肽中硫的铂（二亚乙基三胺）（Pt(dien)SG）和单官能团结合到S-甲基谷胱甘肽中硫的铂（二亚乙基三胺）（Pt(dien)SMeG））研究了调节剂WR2721、其活性硫醇代谢物WR1065和对称二硫化物WR33278对顺铂-蛋白质相互作用的可逆性。两种模型化合物都可以通过高效液相色谱（HPLC）结合紫外检测进行定量。Pt(dien)SG中类似铂-半胱氨酸的键不能被任何一种WR化合物或强亲核试剂硫代硫酸盐（TS）和二乙基二硫代氨基甲酸盐（DDTC）逆转。然而，Pt(dien)SMeG中类似铂-甲硫氨酸的键可以被WR1065逆转，尽管与使用调节剂TS（k2 = 10.1 M-1 s-1）和DDTC（k2 = 3.66 M-1 s-1）相比，逆转速度较慢（k2 = 0.142 M-1 s-1）。WR2721几乎不能逆转Pt(dien)SMeG中的铂-硫键（k2 = 0.00529 M-1 s-1），WR33278也没有这样的能力。与强亲核试剂DDTC（2 mM DDTC时为61%）相比，任何一种WR化合物（20 mM WR1065、WR2721和WR33278分别为16%、7.7%和0）都不能明显恢复顺二氯二氨铂（II）（CDDP）失活的延胡索酸酶的活性。这些体外研究在分子水平上提供了信息，这可能解释了为什么与DDTC相比，WR2721在含铂化疗后给药时不能预防顺铂诱导的肾毒性。结果支持了WR2721在铂化合物给药前的当前临床应用。
