Expression of the c-Ha-ras Oncogene in Mouse NIH 3T3 Cells Induces Resistance to Cisplatin

Seiji Isonishi, Doreen K. Horn, Franz B. Thiebaut, Stephen C. Mann, Paul A. Andrews, Stephen B. Howell, Alakananda Basu, John S. Lazo, Alan Eastman, Stephen B. Howell

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The effect of expression of the c-l la-ra.s oncogene on cisplatin (DDP) sensitivity was examined in murine NIH 3T3 cells transfected with the dexamethasone (DEX)-inducible mouse mammary tumor virus promoter linked to an activated c-Ha-rai gene [LTR H-ras(A) cells]. Treatment of these cells with 5 JJMDEX for 24 h induced c-Ha-ras expression and produced an 8.2 ±1.3-fold (SD) increase in DDP resistance as quantitated by clonogenic assay. Induction of the c-Ha-ra? oncogene reduced DDP accumulation by 40% and intrastrand adduct formation by 17%. In nontransfected wild-type NIH 3T3 cells, DEX did not induce DDP resistance nor did it decrease DDP accumulation. Induction of c-Ha-ras expression did not alter cellular glutathione content or the activity of glutathione-5-transferase in the LTR H-ras(A) cells. DEX increased cellular metallothionein content by 1.6-fold in NIH 3T3 cells and 3.3- fold in LTR H-ras(A) cells. We conclude that DEX-induced overexpression of a mutant c-Ha-ras gene confers DDP resistance and that this resistance is associated with an impairment of cellular drug accumulation and an increase in metallothionein content.

Original languageEnglish
Pages (from-to)5903-5909
Number of pages7
JournalCancer Research
Issue number21
StatePublished - Nov 1991


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