Suppression of Dexamethasone-induced Metallothionein Expression and as-Diamminedichloroplatinum(II) Resistance by \-mos1

Metallothionein has been implicated in resistance to anticancer drugs. We examined whether transient induction of metallothionein by dexamethasone causes resistance to m-diamininedichloroplatinum(II) (cisDDP) in malignant and nonmalignant cells. Normal rat kidney cells (6m2) were infected with a modified \-mos oncogene construct in which expression of \-mos and consequently transformation was temperaturesensitive occurring at the permissive temperature of <33°C and not at the nonpermissive temperature of 37°C.Temperature-sensitive oncogenic transformation by \-mos attenuated induction of metallothionein by dexamethasone. No induction of metallothionein was observed in a revertant 6m2 cell line (54-5A4), which expressed v-m».vand was transformed at 37°C.Only nontransformed 6m2 cells displayed resistance to cis-DDP after dexamethasone pretreatment for 24 h. Dexamethasone pretreatment did not cause marked resistance to doxorubicin or melphalan in nontrans formed 6m2 cells. When 6m2 cells (37°C) were pretreated with dexa methasone (0.5 MM)for 24 h and then incubated in dexamethasone-free medium for 24 h, both metallothionein levels and resistance to c/.v-l)!)!' decreased significantly. Thus, transient resistance to cÃ-Ã--DDPcan be produced by a nonmetal inducer of metallothionein in nontransformed cells. Glucocorticoid-induced protection is suppressed in cells expressing \-mos and this might form the basis of future strategies to improve the therapeutic index of cw-DDP.