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result sql = Is glutathione the major cellular target of cisplatin? A study of the interactions of cisplatin with cancer cell extracts.
Is glutathione the major cellular target of cisplatin? A study of the interactions of cisplatin with cancer cell extracts.
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result sql = Cisplatin is an anticancer drug whose efficacy is limited because tumors develop resistance to the drug. Resistant cells often have elevated levels of cellular glutathione (GSH), believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly, forming [Pt(SG)(2)] adducts. We show by [(1)H,(15)N] HSQC that the half-life of (15)N labeled cisplatin in whole cell extracts is approximately 75 min, but no Pt-GSH adducts were observed. When the low molecular mass fraction (<3 kDa) of the extracts was incubated with cisplatin, binding to GSH was observed probably due to removal of high molecular mass platinophiles. Two-thirds of the Pt adducts formed in whole cell extracts, had a molecular mass >3 kDa. [Pt(SG)(2)] cannot account for more than 20% of the Pt adducts. The concentration of reduced thiols in the high molecular mass fraction of the extracts is six times higher than in the low molecular mass fraction.

Publication: J. Med. Chem. 2009 Jul 23 ;52(14)::4319-28. :doi: 10.1021/jm900138u.
Publication Date: 2009 Jul 23
Study Author(s): Kasherman, Yonit;Sturup, Stefan;Gibson, Dan;
Institution: Faculty of Pharmaceutical Sciences, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.
Shortcut link to this study:
Cisplatin is an anticancer drug whose efficacy is limited because tumors develop resistance to the drug. Resistant cells often have elevated levels of cellular glutathione (GSH), believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly, forming [Pt(SG)(2)] adducts. We show by [(1)H,(15)N] HSQC that the half-life of (15)N labeled cisplatin in whole cell extracts is approximately 75 min, but no Pt-GSH adducts were observed. When the low molecular mass fraction (<3 kDa) of the extracts was incubated with cisplatin, binding to GSH was observed probably due to removal of high molecular mass platinophiles. Two-thirds of the Pt adducts formed in whole cell extracts, had a molecular mass >3 kDa. [Pt(SG)(2)] cannot account for more than 20% of the Pt adducts. The concentration of reduced thiols in the high molecular mass fraction of the extracts is six times higher than in the low molecular mass fraction.
PMID: 19537717

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