A chemical mechanism for inactivation of anticancer drugs by metallothionein

A role for inducible metallothionein in acquired drug resistance has been proposed by several laboratories [1, 2 and others]. We have undertaken to test the hypothesis that deactivation of therapeutic alkylating agents occurs by covalent sequestration by metallothionein. We propose that these reactions make zinc more available to activate the regulatory elements that control transcription and, in turn, the synthesis of more protein. It should be pointed out that other inducible proteins are already considered to act in acquired drug resistance, including glycoprotein-53, and the glutathione-S-transferase family. The latter inactivates therapeutic nitrogen mustards by catalyzing covalent bond formation with the thiol group of the cofactor glutathione.