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

Marco Treskes, Ulbe Holwerda, Leo G J Nijtmans, Herbert M. Pinedo, Wim J F van der Vijgh

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)467-470
Number of pages4
JournalCancer Chemotherapy and Pharmacology
Volume29
Issue number6
DOIs
StatePublished - Nov 1992
Externally publishedYes

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Ditiocarb
Metabolites
Cisplatin
Sulfur
Thiosulfates
Nucleophiles
Proteins
Glutathione
Fumarate Hydratase
Platinum Compounds
Chemotherapy
High performance liquid chromatography
Platinum
Sulfhydryl Compounds
Disulfides
Cysteine
High Pressure Liquid Chromatography
WR 1065
Drug Therapy
chlorodiethylenetriamine platinum(II)-S-methyl-glutathione complex

ASJC Scopus subject areas

  • Pharmacology
  • Oncology
  • Cancer Research

Cite this

The reversal of cisplatin-protein interactions by the modulating agent WR2721 and its metabolites WR1065 and WR33278. / Treskes, Marco; Holwerda, Ulbe; Nijtmans, Leo G J; Pinedo, Herbert M.; van der Vijgh, Wim J F.

In: Cancer Chemotherapy and Pharmacology, Vol. 29, No. 6, 11.1992, p. 467-470.

Research output: Contribution to journalArticle

Treskes, Marco ; Holwerda, Ulbe ; Nijtmans, Leo G J ; Pinedo, Herbert M. ; van der Vijgh, Wim J F. / The reversal of cisplatin-protein interactions by the modulating agent WR2721 and its metabolites WR1065 and WR33278. In: Cancer Chemotherapy and Pharmacology. 1992 ; Vol. 29, No. 6. pp. 467-470.
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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 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.",
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