Metallothionein and anticancer agents: the role of metallothionein in cancer chemotherapy

Metallothioneins (MTs) are intracellular proteins containing the highest amount of thiol groups within the cytoplasm. These thiol groups are able to bind several cytotoxic agents, such as platinum compounds and alkylating agents. Increased levels of MT are one mechanism of resistance to these anticancer drugs, as intracytoplasmic binding of MT prevents the active molecules from reaching their target, the intranuclear DNA of tumor cells. MT synthesis can easily be induced by physiologic heavy metals such as zinc and copper. Pharmacological modulation of MT levels has been used to increase the MT pool in normal tissues and decrease their susceptibility to the toxicity of anticancer drugs. In the case of tumors arising in the brain, where the inducibility of MT synthesis is low, this approach would allow protection of normal tissues without decreasing the antitumor activity of the cytotoxic agents. The interaction of MT with cytotoxic agents is not limited to covalent binding. A correlation between MT synthesis and amplification of oncogenes such asras has been reported. Furthermore, the cytotoxic drugs are bound by MT after competition with zinc and copper; these metals are cofactors of numerous metalloenzymes, some of which are involved in the metabolism of nucleic acids. Competitive displacement of these metals might modify nucleic acid metabolism and influence cellular proliferation. On the other hand, increased MT levels could provide a zinc cofactor reserve that increases the cell's reparative potential when faced by DNA damage by cytotoxic agents. Although the physiologic role of MT in resistance to the cytotoxic effects of anticancer drugs remains unclear, a better understanding of the interaction between MT and chemotherapeutic agents may be important in the treatment of cancer.