TY - JOUR
T1 - Farnesyl thiosalicylic acid chemosensitizes human melanoma in vivo.
AU - Halaschek-Wiener, Julius
AU - Kloog, Yoel
AU - Wacheck, Volker
AU - Jansen, Burkhard
N1 - Funding Information:
We thank the members of the Center for Biomedical Research at the University of Vienna, and in particular Dr H. Bergmeister and H. Pischinger, for outstanding animal care and continuing support. We are grateful to Thyreos Corporation for the supply of CRYSMEB and FTS, and we thank S. Smith for editorial assistance. The work in the laboratory of B.J. was supported by the Austrian Science Fund (FWF), the Austrian National Bank, and the Kamillo Eisner Stiftung. The work in the laboratory of Y.K. was supported by the SFAHO fund.
PY - 2003/1
Y1 - 2003/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84966277020&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1747.2003.12009.x
DO - 10.1046/j.1523-1747.2003.12009.x
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AN - SCOPUS:84966277020
SN - 0022-202X
VL - 120
SP - 1
EP - 7
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 1
ER -
