Activated N-ras contributes to the chemoresistance of human melanoma in severe combined immunodeficiency (SCID) mice by blocking apoptosis.
Activation of the N-ras gene by point mutations occurs in about 15 % of all human melanomas. Using recently established melanoma severe combined immunodeficiency-human mouse xenotransplantation models, here we further investigate the biological significance of these mutations. We demonstrate that activated N-ras significantly contributes to the chemoresistance of human melanoma both in vitro and in vivo by blocking apoptosis. Overexpression of wild-type N-ras had no such effects. With antisense oligonucleotides and farnesyltransferase inhibitors, tools capable of blocking Ras function on the therapeutic horizon, our observation that activated N-ras is not a bystander but a factor worth targeting to improve therapeutic outcome in melanoma gains additional importance.
Jansen
B
B
Department of Clinical Pharmacology, Section of Experimental Oncology, Vienna, Austria.
Schlagbauer-Wadl
H
H
Eichler
H G
HG
Wolff
K
K
van Elsas
A
A
Schrier
P I
PI
Pehamberger
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D017354:Point Mutation; D014407:Tumor Cells, Cultured
D002945:Cisplatin