Novel Ras antagonist blocks human melanoma growth

During past decades, knowledge of melanoma biology has increased considerab ly. Numerous therapeutic: modalities based on this knowledge are currently under investigation. Advanced melanoma, nevertheless, remains a prime examp le of poor treatment response that may, in part, be the consequence of acti vated N-Ras oncoproteins. Besides oncogenic Ras, wild-type Ras gene product s also play a key role in receptor tyrosine kinase growth factor signaling, known to be of importance in oncogenesis and tumor progression of a variet y of human neoplasms, including malignant melanoma; therefore, it is reason able to speculate that a pharmacological approach that curtails Ras activit y may represent a sensible approach to inhibit melanoma growth. To test thi s concept, the antitumor activity of S-trans, trans-farnesylthiosalicylic a cid (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 xenotrans plantation models of human melanoma expressing either wild-type Ras (cell l ine 518A2) or activated Ras (cell line 607B). We show that FTS (5-50 mu M) reduces the amounts of activated N-Ras and wild-type Ras isoforms both in h uman melanoma cells and Rat-1 fibroblasts, interrupts the Ras-dependent ext racellular signal-regulated kinase in melanoma cells, inhibits the growth o f N-Ras-transformed fibroblasts and human melanoma cells in vitro and rever ses their transformed phenotype. FTS also causes a profound and statistical ly significant inhibition of 518A2 (82%) and 6078 (90%) human melanoma grow th in SCID mice without evidence of drug-related toxicity. Our findings str ess the notion that FTS may qualify as a novel and rational treatment appro ach for human melanoma and possibly other tumors that either carry activate d ras genes or rely on Ras signal transduction more heavily than nonmaligna nt cells.