Malignant melanoma is well known for its poor response to a variety of chemotherapeutic agents. Testing of numerous treatment strategies has identified dacarbazine as the most active single drug; however, its response rates in various clinical settings are quite limited. Defective apoptosis in combination with oncogenic proteins (such as activated Ras) in cell proliferation pathways plays a key part in both the development and disease progression of human melanoma. Farnesyl thiosalicylic acid, a novel Ras inhibitor, dislodges Ras proteins from the cell membrane, leading to inhibition of cell transformation and tumor growth. In this study we evaluated the effect of farnesyl thiosalicylic acid treatment on established human melanoma xenografts grown in mice with severe combined immunodeficiency as well as the chemosensitizing effect of farnesyl thiosalicylic acid in combination with dacarbazine. Daily administration of 10, 20, or 40 mg per kg of farnesyl thiosalicylic acid resulted in a concentration-dependent reduction in tumor growth, with growth inhibition reaching a mean value of 45+/-7%, at the highest concentration. The combination of farnesyl thiosalicylic acid (10 mg per kg per day) and dacarbazine (80 mg per kg per day) resulted in a significant reduction of 56%+/-9%, in mean tumor growth. Analysis of toxicologic parameters (mouse weight, blood cell counts, and blood chemistry) showed an acceptable and similar toxicity profile for both the single-agent farnesyl thiosalicylic acid treatment and the combination of farnesyl thiosalicylic acid plus dacarbazine treatment. Given the observed preclinical treatment responses and the low toxicity, our results support the notion that farnesyl thiosalicylic acid in combination with dacarbazine may qualify as a rational treatment approach for human melanoma.