In our efforts to investigate the biologic role of Ha-rasoncogenes in human melanoma by Ha-rasphosphorothioate antisense oligonucleotides, we observed that antisense, sense, and scrambled control oligonucleotides at a concentration of 10 μM all similarly and strongly inhibited growth of our human melanoma target cell line SK-2in vitrobut without specific decrease of the target protein. Cell numbers with respect to the untreated control were reduced by 84% ± 4.2% (ISD), 82.9% ± 3.6%, and 84% ± 3%, respectively.In vivostudies in a SCID-hu mouse model confirmed these findings. Both antisense and sense control oligonucleotides administered through osmotic pumps significantly (p<0.006) reduced the mean tumor weight (1.5 g ± 0.4 g and 1.8 g ± 0.8 g, respectively) in comparison with saline-treated (5.7 g ± 0.7 g) or untreated control animals (5.8 g ± 1.0 g). The vascularity of oligonucleotide-treated tumors was greatly reduced. Clinical signs of oligonucleotide-related toxicity were not observed, and there was no evidence of histopathologic alterations in a variety of mouse tissues. We could demonstrate that the antimelanoma effects can be abrogatedin vitroby adding basic fibroblast growth factor (bFGF). In the context of the importance of bFGF in melanocyte biology and angiogenesis, we argue in favor of an interaction between polyanionic phosphorothioate oligonucleotides and bFGF in our melanoma system. These findings stress the notion that phosphorothioate oligonucleotides may be promising antineoplastic lead compounds capable of employing antitumor effects by mechanisms other than specific inhibition of gene exp