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Suppression of Dexamethasone-induced Metallothionein Expression and cis-Diamminedichloroplatinum(II) Resistance by v-mos¹

Department of Pharmacology, University of Pittsburgh School of Medicine, and Experimental Therapeutics Program, Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15261

Metallothionein has been implicated in resistance to anticancer drugs. We examined whether transient induction of metallothionein by dexamethasone causes resistance to cis-diamminedichloroplatinum(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 temperature-sensitive 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-mos and 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 nontransformed 6m2 cells. When 6m2 cells (37°C) were pretreated with dexamethasone (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 cis-DDP can 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 cis-DDP.

¹ This work was supported by NIH Grant CA-43917 and a grant (100-R061) from the Bristol-Myers Squibb Co.

² To whom requests for reprints should be addressed, at E1346 Biomedical Science Tower, Department of Pharmacology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261.

Received 8/ 9/90. Accepted 11/20/90.