Abstract

Evidence has been presented both that metallothionein does and does not produce resistance to cisplatin. The metallothionein-enriched cells described in most previous studies have been selected for resistance to heavy metals, such as cadmium, or have been maintained in a medium enriched for the metals. Exposure to toxic metals could alter the cells in many ways. This report addresses the effect of metallothionein content alone, independent of exposure to metals, on cellular resistance to cisplatin. The toxicity of cisplatin was compared in NIH/3T3 cells that vary in their content of metallothionein as a consequence of transfection with a plasmid that results in the constitutive expression of metallothionein. The plasmid contains the bovine papillomavirus genome and the mouse metallothionein-I gene; it is driven by a glucose-regulated protein of 78 kD. Control cells were transfected with a similar plasmid in which the coding sequences for metallothionein were inverted and separated from the promoter, thereby abolishing expression. Expression of metallothionein required neither selection nor maintenance of cells in the presence of heavy metals. Despite large differences between the two types of cells in their cellular content of metallothionein and in their resistance to the toxicity of cadmium, no differences in resistance to cisplatin were observed.