Abstract
Intrinsic and acquired resistance to antineoplastic agents has severely limited our ability to cure solid tumors. Cis-diamminedichloroplatinum (cisplatin) represents one of the most efficacious agents for the treatment of solid tumors especially testicular, ovarian, bladder, and head and neck carcinomas. Once this neutral compound enters cells, the chloride ligands are exchanged for water or hydroxyl moieties and a biologically reactive bifunctional electrophile is produced. Like most of our effective antineoplastic agents, this aquated platinum compound can react with intracellular nucleophiles. Although only approximately 1% of the intracellular drug covalently reacts with DNA, there is extensive evidence implicating genomic DNA as the critical target for its cytotoxicity (Roberts and Thomson, 1979).
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Andrews, P.A., Murphy, M.P., and Howell, S.B., 1987, Metallothionein-mediated cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother. Pharmacol. 19:149–154.
Bakka, A., Endresen, L., Johnsen, A.B.S., Edminson, P.D., and Rugstad, H.E., 1981, Resistance against cis-dichlorodiammineplatinum in culture cells with high content of metallothionein. Toxicol. Appl. Pharmacol. 61:215–226.
Basu, A., and Lazo, J.S., 1990, A hypothesis regarding the protective role of metallothioneins against the toxicity of DNA interactive anticancer drugs. Toxicol. Lett. 50:123–135.
Basu, A., and Lazo, J.S., 1991, Suppression of dexamethasone-induced metallothionein expression and cis-diamminedichloroplatinum resistance by v-mos. Cancer Res. 51:893–896.
Borch, R.F., 1987, The platinum anti-tumor drugs. In: G. Powis and R. Prough (Eds.), Metabolism and Action of Anti-cancer Drugs. Taylor and Francis, Ltd., London, pp. 163–193.
Chin K-V., Chauhan, S.S., Pastan, I., and Gottesman, M.M., 1990, Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells. Cell Growth Differentiation 1:361–365.
Churchich, J.E., Scholz, G., and Kwok, F., 1989, Activation of pyridoxal kinase by metallothionein. Biochem. Biophys. Acta. 996:181–186.
De, S.K, McMaster, M.T., and Andrews, G.K., 1990, Endotoxin induction of murine metallothionein gene expression. J. Biol. Chem. 265:15267–15274.
Endresen, L., Bakka, A., and Rugstad, E., 1983, Increased resistance to chlorambucil in cultured cells with a high concentration of cytoplasmic metallothionein. Cancer Res. 43:2918–2926.
Endresen, L., 1984, Comparison of the cytotoxic effect of prednimustine in cultured cells with high or low levels of metallothionein. Acta. Pharmacol. Toxicol. 54:49–57.
Freedman, J.H., Ciriolo, M.R., and Peisach, J., 1989, The role of glutathione in copper metabolism and toxicity. J.Biol. Chem. 264:5598–5605.
Freedman, J., and Peisach, J., 1989, Intracellular copper transport in cultured hepatoma cells. Biochem. Biophys. Res. Comm. 164:134–140.
Hamer, D., 1986, Metallothionein. Annu. Rev. Biochem. 55:913–951.
Hidalgo, J., Garvey, J.S. and Armario, A., 1990, On the metallothionein, glutathione, and cysteine relationship in rat liver. J. Pharmacol. Exptl. Therap. 255:554–564.
Jahroudi, N., Foster, R., Price-Haughey, J., Beitel, G., and Gedamu, L., 1990, Cell-type specific and differential regulation of the human metallothionein genes. J. Biol. Chem. 265:6506–6511.
Kagi J.H.R., and Schaffer, A., 1988, Biochemistry of metallothionein. Biochemistry 27:8509–8515.
Kaina, B., Lohrer, H., Karin, M., and Herrlich, P., 1990, Overexpressed human metallothionein HA gene protects Chinese hamster ovary cells from killing by alkylating agents. Proc. Natl. Acad. Sci. USA 87:2710–2714.
Kelley, S.L., Basu, A., Teicher, BA, Hacker, M.P., Hamer, D.H., and Lazo, J.S., 1988, Overexpression of metallothionein confers resistance to anticancer drugs. Science 241:1813–1815.
Klaassen C.D., and Lehman-Mckeeman, L.D., 1989, Induction of metallothionein. J. Am. College Toxicol. 8:1315–1321.
Lohrer, H., Robson, T., Grindley, H., Foster, S., and Hall, A., 1990, Differential effects on cell killing in metallothionein overexpressing CHO mutant cell lines. Carcinogenesis 11:1937–1941.
Lohrer, H., and Robson, T., 1989, Overexpression of metallothionein in CHO cells and its effect on cell killing by ionizing radiation and alkylating agents. Carcinogenesis 10:2279–2284.
Margoshhes, M. and Vallee, B.L., 1957, A cadmium protein from equine kidney cortex. J. Am. Chem. Soc. 79:4813–4814.
Mason, R., Edwards, I.R., and McLarsen, S.J., 1984, Interaction of platinum with metallothionein-like ligands in the rat kidney after adminstration of cis-dichlorodiammine platinum II. Chem.-Biol. Interact. 49:165–179.
Naganuma, A., Satoh, M., Koyama, Y., and Imura, N., 1985, Protective effect of metallothionein inducing metals on the toxicity of cis-diamminedichloroplatinum in mice. Toxicol Lett 24:203–207.
Naganuma, A., Satoh, M., and Imura, N., 1987, Prevention of lethal and renal toxicity of cis-diamminedichloro-platinum(II) by induction of metallothionein synthesis without compromising its antitumor activity in mice. Cancer Res. 4:983–987.
Nartey, N.O., Banerjee, D., and Cherian, G., 1987, Immunohistochemical localization of metallothionein in cell nucleus and cytoplasm of fetal human liver and kidney and its changes during development. Pathology 19:233–238.
Nartey, N., Cherian, M.G., and Banerjee, D., 1987, Immunohistochemical localization of metallothionein in human thyroid tumors. Am. J. Pathol. 129:177–182.
Otvos, J.D., Petering, D.H., Shaw, C.F., 1989, Structure-reactivity relationships of metallothionein, a unique metal-binding protein. Comments Inorg. Chem. 9:1–34.
Roberts, J.J. and Thomson, A.J., 1979, The mechanism of action of antitumor platinum compounds. Prog. Nucleic Acid Res. Mol. Biol. 22:71–133.
Schilder, R.J., Hall, L., Monks, A, Handel, L.M., Fornace Jr., A.J., Ozols, R.F., Fojo, AT., and Hamilton, T.C., 1990, Metallothionein gene expression and resistance to cisplatin in human ovarian cancer. Int. J. Cancer 45:416–422.
Schmidt, C.J., and Hamer, D.H., 1986, Cell specificity and an effect of ras on human metallothionein gene expression. Proc. Natl. acad. Sci. USA 83:3346–3350.
Sharma, R.P., and Edwards, I.R., 1983, Cis-platinum: subcellular distribution and binding to metallothionein. Toxicol. Appl. Pharmacol 51:19–27.
Teicher, B.A., Holden, S.A, Kelley, M.J., Shea, Th.C., Cucchi, C.A., Rosowsky, A, Henner, W.D., and Frei III, E., 1987, Characterization of a human squamous carcinoma cell line resistant to cis-diamminedichloroplatinum (II). Cancer Res. 47:388–393.
Zelazowski, AJ., Garvey, J.S., and Hoeschaele, J.D., 1984 In vivo and in vitro binding of platinum to metallothionein. Arch. Biochem. Biophys. 229:246–252.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1991 Springer Science+Business Media New York
About this chapter
Cite this chapter
Lazo, J.S. (1991). Metallothioneins and Cisplatin Resistance. In: Howell, S.B. (eds) Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0738-7_29
Download citation
DOI: https://doi.org/10.1007/978-1-4899-0738-7_29
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-0740-0
Online ISBN: 978-1-4899-0738-7
eBook Packages: Springer Book Archive