Expression of the c-Ha-ras oncogene in mouse NIH 3T3 cells induces resistance to cisplatin.
The effect of expression of the c-Ha-ras 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-ras gene [LTR H-ras(A) cells]. Treatment of these cells with 5 microM DEX 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-ras 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-S-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.
Isonishi
S
S
Department of Medicine, University of California, San Diego, La Jolla 92093.
Hom
D K
DK
Thiebaut
F B
FB
Mann
S C
SC
Andrews
P A
PA
Basu
A
A
Lazo
J S
JS
Eastman
A
A
Howell
S B
SB
D016475:3T3 Cells; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D011905:Genes, ras; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D010957:Plasmids; D011401:Promoter Regions, Genetic; D014162:Transfection
D003907:Dexamethasone; D002945:Cisplatin