Cisplatin detoxification

A major component of the intracellular protein thiol pool is the class of inducible, cysteine-rich metallothionein (MT) proteins, important in heavy metal detoxification in eucaryotes (52). Studies of a human head and neck carcinoma cell line revealed no difference in nonprotein sulfhydryl content between parental cells and cells 30-fold resistant to cisplatin, but the latter had twofold greater levels of total protein sulfhydryl content (127). Several human and murine tumor cell lines resistant to cisplatin showed increased expression of one metallothionein, MT Ila, and increased levels of the protein (68). In addition, mouse cells transfected with the gene encoding metallothionein Ila showed a 10-fold increase in the level of MT accompanied by a 4.4-fold level of resistance to cw-DDP (68). By contrast, treatment of rats with cisplatin followed by chromatographic resolution of kidney metallothioneins showed that platinum did not elute with the MT fractions (84). Moreover, pretreatment of rats with Cd-" to induce MT production had no effect on the metabolism of platinum in kidney or liver (84). In vitro studies of the relative affinity of Cu-metallothionein for a variety of metal ions revealed very weak binding of divalent platinum... 

An in vitro study found that megestrol may antagonise the antineoplastic activity of cisplatin by up-regulating cellular detoxification mechanisms. ... 

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