Cisplatin glutathione

See also Carbon Tetrachloride Cephalosporins Chloroform Cisplatin Glutathione Metals Penicillin. 

Glutathione readily replaces the GSMe on platinum in the reaction with [Pt(dien)(GSMe)]2+ (GSMe = S-methylglutathione) - this system is claimed to be an effective model for cisplatin-protein interaction 224). Rate constants and activation parameters have been... 

Intracellular thiolate ligands such as glutathione (GSH, the tripeptide y-L-Glu-L-Cys-Gly) are believed to inactivate cisplatin because the reactions with cisplatin tend to be irreversible (35). Elevated levels of GSH have been observed in cisplatin-resistant cells. Recently, it has been shown that an MRP gene, which encodes a human ATP-dependent glutathione S-conjugate export pump (GS-X pump), is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells (36). The GS-X pump may contribute to the excretion of Pt-GS complexes from cells (37). 

In human plasma at 37°, the disappearance of cisplatin occurred with a tl/2 value of 1.3 h. Kinetics analysis demonstrated that the major components of reaction were formation of hydrated species (tl/2 3.4 h), irreversible binding to proteins (t1/2 2.1 h), and formation of mobile conjugates (e.g., with glutathione t1/2 24 h) [185], A very large quantity of relevant data are compiled in [181],... 

Possible biochemical mechanisms of resistance to alkylating agents include changes in ceU DNA repair capability, increases in cell thiol content (which in turn can serve as alternative and benign targets of alkylation), decreases in ceU permeability, and increased activity of glutathione transferases. Increased metaUothionein content has been associated with tumor cell resistance to cisplatin. 

It was early determined that in the cell, the electrophilic species derived from cisplatin bind to three major targets RNA (which is present at high concentration in cytoplasm, together with nucleoproteins) (50%), DNA (40%) and proteins (10%) [25]. It also binds to cysteine and methionine residues of proteins, to metallothioneins, glutathione, methionine, and glutamate which are good traps for chloro and/or aqua platinum electrophiles [26],... 

Transplatin reacts 360 times faster than cisplatin with glutathione [27], a reaction likely to remove platinum from the cell, through ATP-dependent efflux [28]. It has been shown that a thioether ligand on a platinum triamine complex can be slowly replaced by a guanine-N(7), suggesting a possible platinum transporter role for such thioether compounds towards DNA [6], (This topic is discussed in the contribution by J. Reedijk and J. M. Teuben.)... 

Reduced reactivity toward sulfur-containing soft nucleophiles relative to cisplatin, including glutathione ... 

In vitro circumvention of acquired cisplatin resistance due to decreased transport, increased glutathione and enhanced DNA repair ... 

Either the catalytic subunit or both subunits are overexpressed in several drug-resistant human cancer cells such as cisplatin-resistant ovarian cancer cells and melphalan-resistant prostate cancer cells, suggesting that elevated production of glutathione may induce drug-resistance mechanisms in these cancer cells (Figure... 

Andrews PA, Schiefer MA, Murphy MP, Howell SB. Enhanced potentiation of cisplatin cytotoxicity in human ovarian carcinoma 42. cells by prolonged glutathione depletion. Chem.-Biol. Interact. 1988 65 51-58. 

Among several thiol compounds, glutathione may provide neuroprotection in patients treated with cisplatin without altering its antineoplastic activity. This protective role may be based on blockade of the accumulation of p53 protein in response to platinum in dorsal root ganglia, thereby hindering platinum-based apoptosis (57,112). 

The mechanisms of cisplatin-induced damage to the outer hairy cells of the cochlea may include the formation of highly reactive oxygen radicals and depletion of glutathione (144). The role of amifostine and glutathione... 

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