Journal of Neuro-Oncology

, Volume 17, Issue 2, pp 123–129 | Cite as

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

  • François Doz
  • Norbert Roosen
  • Mark L. Rosenblum
Laboratory Investigation


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 words

metallothionein brain tumor chemotherapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kägi JHR, Schaffer A: Biochemistry of metallothionein. Biochemistry 27: 8509–8515, 1988PubMedGoogle Scholar
  2. 2.
    Fosmire GJ: Zinc toxicity. Am J Clin Nutr 51: 1225–1227, 1990Google Scholar
  3. 3.
    Felix K, Weser U: Release of copper from yeast copper-thionein after S-alkylation of copper-thiolate clusters. Biochem J 252: 577–588, 1988PubMedGoogle Scholar
  4. 4.
    Webb M: Toxicological significance of metallothionein. Experientia Suppl 52: 109–113, 1987PubMedGoogle Scholar
  5. 5.
    Lazo JS, Bahnson RR: Pharmacological modulators of DNA-interactive antitumor drugs. Trends Pharmacol Sci 10: 369–373, 1989PubMedGoogle Scholar
  6. 6.
    Palmiter RD, Findley SD, Whitmore TE, Durnam DM: MT-III, a brain specific member of the metallothionein gene family. Proc Natl Acad Sci USA 89: 6333–6337, 1992PubMedGoogle Scholar
  7. 7.
    Mayo KE, Palmiter RD: Glucocorticoid regulation of metallothionein-I mRNA in cultured mouse cells. J Biol Chem 256: 2621–2624, 1981PubMedGoogle Scholar
  8. 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
  9. 9.
    Imbra RJ, Karin M: Metallothionein gene expression is regulated by serum factors and activators of protein kinase C. Mol Cell Biol 7: 1358–1363, 1987PubMedGoogle Scholar
  10. 10.
    Abe S, Matsumi M, Tsukioki M, Mizukawa S, Takahashi T, Iijima Y, Itano Y, Kosaka F: Metallothionein and zinc metabolism in endotoxin shock in rats. Experientia Suppl 52: 587–594, 1987PubMedGoogle Scholar
  11. 11.
    Bremner I, Davies NT: The induction of metallothionein by zinc injection and restriction of food intake. Biochem J 149: 733–738, 1975PubMedGoogle Scholar
  12. 12.
    Hidalgo J, Borràs M, Garvey JS, Armario A: Liver, brain, and heart metallothionein induction by stress. J Neurochem 55: 651–654, 1990PubMedGoogle Scholar
  13. 13.
    Zelazowski AJ, Garvey JS, Hoeschele JD:In vivo andin vitro binding of platinum to metallothionein. Arch Biochem Biophys 229: 246–252, 1984PubMedGoogle Scholar
  14. 14.
    Doz F, Berens ME, Deschepper CF, Dougherty DV, Bigornia V, Rosenblum ML: Experimental basis for increasing the therapeutic index of cis-diamminedicarboxylato-cyclobutaneplatinum (II) in brain tumor therapy by a high-zinc diet. Cancer Chemother Pharmacol 29: 219–226, 1992PubMedGoogle Scholar
  15. 15.
    Schmidt CJ, Hamer DH: Cell specificity and an effect ofras on human metallothionein gene expression. Proc Natl Acad Sci USA 83: 3346–3350, 1986PubMedGoogle Scholar
  16. 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
  17. 17.
    Shimizu R, Kubota M, Tanizawa A, Sano H, Kasai Y, Hashimoto H, Akiyama Y, Mikawa H: Inhibition of both etoposide-induced DNA fragmentation and activation of poly (ADP-ribose) synthesis by zinc ion. Biochem Biophys Res Commun 169: 1172–1177, 1990PubMedGoogle Scholar
  18. 18.
    Endresen L, Bakka A, Rugstad HE: Increased resistance to chlorambucil in cultured cells with a high concentration of cytoplasmic metallothionein. Cancer Res 43: 2918–2926, 1983PubMedGoogle Scholar
  19. 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
  20. 20.
    Kelly SL, Basu A, Teicher BA, Hacker MP, Hamer DH, Lazo JS: Overexpression of metallothionein confers resistance to anticancer drugs. Science 241: 1813–1815, 1988PubMedGoogle Scholar
  21. 21.
    Lohrer H, Robson T: Overexpression of metallothionein in CHO cells and its effect of cell killing by ionizing radiation and alkylating agents. Carcinogenesis 10: 2279–2284, 1989PubMedGoogle Scholar
  22. 22.
    Endresen L, Rugstad HE: Protective function of metallothionein against certain anticancer agents. Experientia Suppl 52: 595–602 1987PubMedGoogle Scholar
  23. 23.
    Andrews PA, Murphy MP, Howell SB: Metallothionein-mediated cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 19: 149–154, 1987PubMedGoogle Scholar
  24. 24.
    Bakka A, Endresen L, Johnsen ABS, Edminson PD, Rugstad HE: Resistance against cis-dichloro-diammineplatinum in cultured cells with a high content of metallothionein. Toxicol Appl Pharmacol 61: 215–226, 1981PubMedGoogle Scholar
  25. 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. 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
  27. 27.
    Kraker A, Schmidt J, Krezoski S, Petering DH: Binding of cis-dichlorodiammine platinum (II) to metallothionein in Ehrlich cells. Biochem Biophys Res Commun 130: 786–792, 1985PubMedGoogle Scholar
  28. 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
  29. 29.
    Farnworth P, Hillcoat B, Roos IAG: Metallothionein-like proteins and cell resistance to cis-dichlorodiammineplatinum (II) in L1210 cells. Cancer Chemother Pharmacol 25: 411–417, 1990PubMedGoogle Scholar
  30. 30.
    Schilder RJ, Hall L, Monks A, Handel LM, Fornace AJ Jr, Ozols RF, Fojo AT, Hamilton TC: Metallothionein gene expression and resistance to cisplatin in human ovarian cancer. Int J Cancer 45: 416–422, 1990PubMedGoogle Scholar
  31. 31.
    Tobey RA, Enger MD, Griffith JK, Hildebrand CE: Zincinduced resistance to alkylating agents: lack of correlation between cell survival and metallothionein content. Toxicol Appl Pharmacol 64: 72–78, 1982PubMedGoogle Scholar
  32. 32.
    Farnworth PG, Hillcoat BL, Roos IAG: Metallothionein induction in mouse tissues by cis-dichlorodiammineplatinum (II) and its hydrolysis products. Chem Biol Interact 69: 319–332, 1989PubMedGoogle Scholar
  33. 33.
    Kotsonis N, Klaassen CD: Increase in hepatic metallothionein in rats treated with alkylating agents. Toxicol Appl Pharmacol 51: 19–27, 1979PubMedGoogle Scholar
  34. 34.
    Coleman CN, Bump EA, Kramer RA: Chemical modifiers of cancer treatment. J Clin Oncol 6: 709–733, 1988PubMedGoogle Scholar
  35. 35.
    Kang YJ, Clapper JA, Enger MD: Enhanced cadmium cytotoxicity in A549 cells with reduced glutathione levels is due to neither enhanced cadmium accumulation nor reduced metallothionein synthesis. Cell Biol Toxicol 5: 249–258, 1989PubMedGoogle Scholar
  36. 36.
    Naganuma A, Satoh M, Koyama Y, Imura N: Protective effect of metallothionein-inducing metals on lethal toxicity of cis-diamminedichloroplatinum in mice. Toxicol Lett 24: 203–207, 1985PubMedGoogle Scholar
  37. 37.
    Naganuma A, Satoh M, Imura N: Prevention of lethal and renal toxicity of cis-diamminedichloroplatinum (II) by induction of metallothionein synthesis without compromising its antitumor activity in mice. Cancer Res 47: 983–987, 1987PubMedGoogle Scholar
  38. 38.
    Satoh M, Naganuma A, Imura N: Metallothionein induction prevents toxic side effects of cisplatin and adriamycin used in combination. Cancer Chemother Pharmacol 21: 176–178, 1988PubMedGoogle Scholar
  39. 39.
    Pogach LM, Lee Y, Giglio W, Naumoff M, Huang HFS: Zinc acetate pretreatment ameliorates cisplatin-induced Sertoli cell dysfunction in Sprague-Dawley rats. Cancer Chemother Pharmacol 24: 177–180, 1989PubMedGoogle Scholar
  40. 40.
    Blalock RL, Dunn MA, Cousins RJ: Metallothionein gene expression in rats: Tissue-specific regulation by dietary copper and zinc. J Nutr 118: 222–228, 1988PubMedGoogle Scholar
  41. 41.
    Ebadi M, Swanson S: Characterization of metallothionein-like protein in rat brain. Experientia Suppl 52: 289–291, 1987PubMedGoogle Scholar
  42. 42.
    Lee DY, Brewer GJ, Wang Y: Treatment of Wilson's disease with zinc. VII. Protection of the liver from copper toxicity by zinc-induced metallothionein in a rat model. J Lab Clin Med 114: 639–645, 1989PubMedGoogle Scholar
  43. 43.
    Pullen RGL, Franklin PA, Hall GH:65Zn uptake from blood into brain in the rat. J Neurochem 56: 485–489, 1991PubMedGoogle Scholar
  44. 44.
    Grider A, Bailey LB, Cousins RJ: Erythrocyte metallothionein as an index of zinc status in humans. Proc Natl Acad Sci USA 87: 1259–1262, 1990PubMedGoogle Scholar
  45. 45.
    Harley CB, Menon CR, Rachubinski RA, Nieboer E: Metallothionein mRNA and protein induction by cadmium in peripheral blood leucocytes. Biochem J 262: 873–879, 1989PubMedGoogle Scholar
  46. 46.
    Doz F, Berens ME, Dougherty DV, Rosenblum ML: Comparison of the cytotoxic activities of cisplatin and carboplatin against glioma cell lines at pharmacologically relevant drug exposures. J Neurooncol 11: 27–35, 1991PubMedGoogle Scholar
  47. 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
  48. 48.
    Naganuma A, Satoh M, Imura N: Specific reduction of toxic side effects of adriamycin by induction of metallothionein in mice. Jpn J Cancer Res 79: 406–411, 1988PubMedGoogle Scholar
  49. 49.
    Abel J, de Ruiter N: Inhibition of hydroxyl radical generated DNA degradation by metallothionein. Toxicol Lett 47: 191–196, 1989PubMedGoogle Scholar
  50. 50.
    Thomas JP, Bachowski GJ, Girotti AW: Inhibition of cell membrane lipid peroxidation by cadmium and zinc metallothioneins. Biochim Biophys Acta 884: 448–461, 1986PubMedGoogle Scholar
  51. 51.
    Matsubara J, Tajima Y, Karasawa M: Promotion of radioresistance by metallothionein induction prior to irradiation. Environ Res 43: 66–74, 1987PubMedGoogle Scholar
  52. 52.
    Matsubara J, Shida T, Ishioka K, Egawa S, Inada T, Machido K: Protective effect of zinc against lethality in irradiated mice. Environ Res 41: 558–567, 1986PubMedGoogle Scholar
  53. 53.
    Thornalley PJ, Vasak M: Possible role for metallothionein in protection against radiation induced oxidative stress. Kinetics and mechanism of its reaction with Superoxide and hydroxylls. Biochim Biophys Acta 827: 36–44, 1985PubMedGoogle Scholar
  54. 54.
    Bakka A, Johnsen AS, Endresen L, Rugstad HE: Radioresistance in cells with high content of metallothionein. Experientia 38: 381–383, 1982PubMedGoogle Scholar
  55. 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
  56. 56.
    Sklar MD: Increased resistance to cis diamminedichloroplatinum (II) in NIH 3T3 cells transformed byras oncogenes. Cancer Res 48: 793–797, 1988PubMedGoogle Scholar
  57. 57.
    Basu A, Lazo JS: Suppression of dexamethasone-induced metallothionein expression and cis-diamminedichloroplatinum (II) resistance byv-mos. Cancer Res 51: 893–896, 1991PubMedGoogle Scholar
  58. 58.
    Kinzler KW, Ruppurt JM, Bigner SH, Volgelstein B: Thegli gene is a member of the Kruppel family of zinc finger proteins. Nature 332: 371–374, 1988PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1993

Authors and Affiliations

  • François Doz
    • 1
  • Norbert Roosen
    • 2
  • Mark L. Rosenblum
    • 2
  1. 1.Service d'Oncologie Pédiatrique and the Laboratoire de Pharmacocinétique Clinique et ExpérimentaleInstitut CurieParisFrance
  2. 2.Department of Neurological SurgeryHenry Ford HospitalDetroitUSA

Personalised recommendations