Metallothionein and anticancer agents: the role of metallothionein in cancer chemotherapy
- 128 Downloads
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.
Key wordsmetallothionein brain tumor chemotherapy
Unable to display preview. Download preview PDF.
- 2.Fosmire GJ: Zinc toxicity. Am J Clin Nutr 51: 1225–1227, 1990Google Scholar
- 8.Cousins RJ, Leinart AS: Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1. FA-SEB J 2: 2884–2890, 1988Google Scholar
- 16.Sharma RP: Interactions of cis-platinum with cellular zinc and copper in rat liver and kidney tissues. Pharm Res Commun 17: 197–206, 1985Google Scholar
- 19.Endresen L: Comparison of the cytotoxic effect of prednimustine in cultured cells with high or low levels of metallothionein. Acta Pharmacol Toxicol 54: 49–57, 1984Google Scholar
- 25.Endresen L, Schjerven L, Rugstad HE: Tumours from a cell strain with a high content of metallothionein show enhanced resistance against cis-dichlorodiammineplatinum. Acta Pharmacol Toxicol 55: 183–187, 1984Google Scholar
- 26.Lazo JS, Basu A, Schultze RL, Reffner BE: Human metallothionein isoforms and resistance to X-irradiation and cisdiamminedichloroplatinum (Abstract). Proc Am Assoc Cancer Res 31: 335, 1990Google Scholar
- 28.Litterst CL, Bertolero F, Uozumi J: The role of glutathione and metallothionein in the toxicity and subcellular binding of cisplatin. In: McBrien DCH, Slater TF (eds) Mechanisms of Platinum Antitumour Drugs. IRL Press, Oxford, 1986, pp 227–248Google Scholar
- 47.Roosen N, Graham TW, Doz F, Berens ME, Dougherty DV, Uriu-Hare JY, Keen CL, Rosenblum ML: Bone marrow protection by zinc pretreatment can increase the therapeutic index of carmustine and carboplatin glioma chemotherapy. Proc Am Assoc Cancer Res 33: 418, 1992 (Abstr)Google Scholar
- 55.Mattern MR, Tan KB, Zimmerman JP, Mong SM, O'Leary Bartus O, Hofmann GA, Drake FH, Johnson RK, Crooke ST, Mirabelli CK: Evidence for the participation of topoisomerases I and II in cadmium-induced metallothionein expression in Chinese hamster ovary cells. Anticancer Drug Des 4: 107–124, 1989PubMedGoogle Scholar