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Metallothionein Null Cells Have Increased Sensitivity to Anticancer Drugs¹

Department of Pharmacology, School of Medicine [Y. K., E. W., J. S. L.], and the Experimental Therapeutics Program of the Pittsburgh Cancer Institute [J. S. L.], University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and The Murdoch Institute for Research into Birth Defects, Parkville, Australia [A. E. M., K. H. A. C.]

Overexpression of metallothioneins (MTs) protects some cells against heavy metals, mutagens, anticancer agents, and reactive oxygen species. We have examined the effect of the loss of MT expression on the cytotoxicity of anticancer agents and mutagens using embryonic fibroblast cells from transgenic mice with targeted disruptions of MT I and II genes (MT -/-). MT -/- cells expressed no detectable MT. Compared to wild type cells, MT -/- cells showed enhanced sensitivity to a 2-h exposure to cisplatin, melphalan, bleomycin, cytarabine, or N-methyl-N'-nitro-N-nitrosoguanidine but were equally sensitive to doxorubicin and neocarzinostatin. Basal expression of the DNA damage-response genes, gadd 45 and gadd 153, were elevated in MT -/- cells compared to MT +/+ cells. Anticancer drug treatment, however, did not produce a greater increase in gadd 45 or gadd 153 expression in MT null cells compared to MT +/+ cells. These results support the hypothesis that endogenous MT levels affect the sensitivity of mammalian cells to mutagens and clinically important anticancer drugs.

¹ Supported in part by NIH Grants CA61299 and NRSA CA62781.

² To whom requests for reprints should be addressed.

Received 1/12/95. Accepted 3/30/95.

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