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Activated N-Ras Contributes to the Chemoresistance of Human Melanoma in Severe Combined Immunodeficiency (SCID) Mice by Blocking Apoptosis¹

Department of Clinical Pharmacology, Section of Experimental Oncology [B. J., H. S-W., H-G. E.], and Department of Dermatology, Division of General Dermatology [B. J., H. S-W., K. W., H. P.], Währinger Gürtel 18-20, A-1090 Vienna, Austria, and Department of Clinical Oncology, University Hospital Leiden (AZL), 2300 Leiden, the Netherlands [A. v. E., P. I. S.]

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.

¹ Supported by the Austrian Science Foundation (FWF) Grant P09894-Med, the Dreher Stiftung Grant 267/95, and the Dutch Cancer Society (KWF) Grant RUL 92-69.

² To whom requests for reprints should be addressed. Fax: 0043-1-40400-2998.

Received 11/20/96. Accepted 12/19/96.

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