title: Novel Ras antagonist blocks human melanoma growth.
abstract: During past decades, knowledge of melanoma biology has increased considerably. Numerous therapeutic modalities based on this knowledge are currently under investigation. Advanced melanoma, nevertheless, remains a prime example of poor treatment response that may, in part, be the consequence of activated N-Ras oncoproteins. Besides oncogenic Ras, wild-type Ras gene products also play a key role in receptor tyrosine kinase growth factor signaling, known to be of importance in oncogenesis and tumor progression of a variety of human neoplasms, including malignant melanoma; therefore, it is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a sensible approach to inhibit melanoma growth. To test this concept, the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a recently discovered Ras antagonist that dislodges Ras from its membrane-anchoring sites, was evaluated. The antitumor activity of FTS was assessed both in vitro and in vivo in two independent SCID mouse xenotransplantation models of human melanoma expressing either wild-type Ras (cell line 518A2) or activated Ras (cell line 607B). We show that FTS (5-50 microM) reduces the amounts of activated N-Ras and wild-type Ras isoforms both in human melanoma cells and Rat-1 fibroblasts, interrupts the Ras-dependent extracellular signal-regulated kinase in melanoma cells, inhibits the growth of N-Ras-transformed fibroblasts and human melanoma cells in vitro and reverses their transformed phenotype. FTS also causes a profound and statistically significant inhibition of 518A2 (82%) and 607B (90%) human melanoma growth in SCID mice without evidence of drug-related toxicity. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for human melanoma and possibly other tumors that either carry activated ras genes or rely on Ras signal transduction more heavily than nonmalignant cells.
authors.affiliation: Department of Dermatology, Division of General Dermatology, University of Vienna, A-1090 Vienna, Austria. burkhard.jansen@univie.ac.at
authors.forename: B
authors.initials: B
authors.lastname: Jansen
authors.forename: H
authors.initials: H
authors.lastname: Schlagbauer-Wadl
authors.forename: H
authors.initials: H
authors.lastname: Kahr
authors.forename: E
authors.initials: E
authors.lastname: Heere-Ress
authors.forename: B X
authors.initials: BX
authors.lastname: Mayer
authors.forename: H
authors.initials: H
authors.lastname: Eichler
authors.forename: H
authors.initials: H
authors.lastname: Pehamberger
authors.forename: M
authors.initials: M
authors.lastname: Gana-Weisz
authors.forename: E
authors.initials: E
authors.lastname: Ben-David
authors.forename: Y
authors.initials: Y
authors.lastname: Kloog
authors.forename: K
authors.initials: K
authors.lastname: Wolff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008546:Melanoma, Experimental / Q000517:prevention & control*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D051381:Rats; D012459:Salicylates / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D018631:ras Proteins