Metallothionein Null Cells Have Increased Sensitivity to Anticancer Drugs1

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 Ml expression on the cytotoxicity of anticancer agents and mutagens using embryonic fibroblast cells from transgenic mice with targeted disruptions of A/7 / and // 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 /V-metnyl-A"-nitro-iY-mtrosoguanidine 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 47+ cells. These results support the hypothesis that endogenous MT levels affect the sensitivity of mammalian cells to mutagens and clinically im portant anticancer drugs.