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.