ALTERED CISPLATIN AND CADMIUM RESISTANCE AND CELL-SURVIVAL IN CHINESE-HAMSTER OVARY CELLS EXPRESSING MOUSE METALLOTHIONEIN

Metallothionein (MT) proteins are associated with resistance to the to xic effects of heavy metals, chemotherapeutic drugs, and alkylating ag ents. It has been suggested that MT may mediate both resistance to tox ic agents and cellular metal homeostasis. To study the role of MT, we obtained cells expressing a range of MT levels in the absence of heavy metal induction. We co-transfected the eukaryotic G418 resistance vec tor pSV2neo and mouse MT-1 cDNA in a pBR322 vector into Chinese hamste r ovary cells. Of 200 transfected clonal cell populations, five had co nstitutive MT expression ranging from 31 to 87 ng of MT/mg of protein. All five populations had increased resistance to cadmium but were les s resistant to cisplatin than control cells. On the other hand, the le vel of foreign MT expression correlated well with the degree of cispla tin resistance among the five clones. Resistance to ionizing radiation and growth rate in the absence of drug or radiation treatment were no t affected. However, transfected MT gene expression inhibited the abil ity of Chinese hamster ovary cells to form colonies in the absence of toxic drug treatment (r = -0.95). The perturbation of cisplatin sensit ivity after genetic alteration of MT expression indicates a role for M T in drug resistance: however, the fact that transfected MT gene expre ssion decreased rather than increased drug resistance and decreased pl ating efficiency in the absence of drug implies that the role of MT ma y not be one of simply ''scavenging'' toxic molecules. These data sugg est a role for MT in homeostatic cellular processes that, when disturb ed by transfection of active MT genes, have an effect on cellular drug resistance.