Effects of tumor promoters on the frequency of metallothionein I gene amplification in cells exposed to cadmium.

Three potent tumor promoters of different classes, 12-O-tetradecanoylphorbol-13-acetate, dihydroteleocidin B, and aplysiatoxin, and two moderate tumor promoters, mezerein and debromoaplysiatoxin, enhanced the frequency of appearance of cadmium-resistant Chinese hamster lung cells when the cells were exposed to cytotoxic levels of CdCl2. With these compounds, the activity to induce cadmium-resistant cells correlated well with the potency of tumor-promoting activity. Cadmium resistance, which persisted after removal of the tumor promoters, was associated with the overproduction of metallothionein I messenger RNA. The amplified metallothionein I genes were shown by Southern blotting experiments. The relevance of the gene amplification caused by tumor promoters is discussed in relation to cancer development and progression.