Suppression of Dexamethasone-induced Metallothionein Expression and as-Diamminedichloroplatinum(II) Resistance by V-mos

Metallothionein has been implicated in resistance to anticancer drugs. We examined whether transient induction of metallothionein by dexamethasone causes resistance to m-diamininedichloroplatinum(II) (cis- DDP) in malignant and nonmalignant cells. Normal rat kidney cells (6m2) were infected with a modified v-mos oncogene construct in which expression of v-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 v-mos attenuated induction of metallothionein by dexamethasone. No induction of metallothionein was observed in a revertant 6m2 cell line (54-5A4), which expressed v-mâ».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 µM)for 24 h and then incubated in dexamethasone-free medium for 24 h, both metallothionein levels and resistance to cis-DDP decreased significantly. Thus, transient resistance to cãÃ- DDPcan be produced by a nonmetal inducer of metallothionein in nontransformed cells. Glucocorticoid-induced protection is suppressed in cells expressing v-mos and this might form the basis of future strategies to improve the therapeutic index of cw-DDP.