METALLOTHIONEIN NULL-CELLS HAVE INCREASED SENSITIVITY TO ANTICANCER DRUGS

Overexpression of metallothioneins (MTs) protects some cells against h eavy metals, mutagens, anticancer agents, and reactive oxygen species. We have examined the effect of the loss of MT expression on the cytot oxicity of anticancer agents and mutagens using embryonic fibroblast c ells from transgenic mice with targeted disruptions of MT I and II gen es (MT -/-). MT -/- cells expressed no detectable MT. Compared to wild type cells, MT -/- cells showed enhanced sensitivity to a 2-h exposur e to cisplatin, melphalan, bleomycin, cytarabine, or N-methyl-N'-nitro -N-nitrosoguanidine but were equally sensitive to doxorubicin and neoc arzinostatin. Basal expression of the DNA damage-response genes, gadd 45 and gadd 153, were elevated in MT -/- cells compared to MT +/+ cell s. Anticancer drug treatment, however, did not produce a greater incre ase in gadd 45 or gadd 153 expression in MT null cells compared to MT +/+ cells. These results support the hypothesis that endogenous MT lev els affect the sensitivity of mammalian cells to mutagens and clinical ly important anticancer drugs.