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.