Therapeutic targeting of the endothelin a receptor in human ovarian carcinoma.

Abstract

The endothelin A receptor (ET(A)R) autocrine pathway is overexpressed in many malignancies, including ovarian carcinoma. In this tumor, engagement of ET(A)R triggers tumor growth, survival, neoangiogenesis, and invasion. To evaluate whether ET(A)R represents a new target in cancer treatment, we examine in vitro and in vivo the effect of the selective ET(A)R antagonist ABT-627 (atrasentan), a small p.o. bioavailable molecule, in mono- and combination therapy with taxane. ABT-627 effectively inhibits cell proliferation, vascular endothelial growth factor (VEGF) secretion of ovarian carcinoma cell lines, and primary cultures. ET(A)R blockade also results in the sensitization to paclitaxel-induced apoptosis. In ovarian carcinoma xenografts, in which the ET-1/ET(A)R autocrine pathway is overexpressed, tumor growth was significantly inhibited in ABT-627-treated mice compared with control. The therapeutic efficacy of ABT-627 was associated with a significant reduction in microvessel density, expression of VEGF, and matrix metalloproteinase-2, and increased the percentage of apoptotic tumor cells. Combined treatment of ABT-627 with paclitaxel produced additive antitumor, apoptotic, and antiangiogenic effects. These findings demonstrate that the small molecule ABT-627 is a candidate for clinical testing as an antitumor agent in ovarian cancer patients, especially in combination with taxane therapy. Interruption of ET(A)R signaling therefore, represents, a promising therapeutic strategy in ovarian carcinoma.

• Authors: Laura Rosanò, Francesca Spinella, Debora Salani, Valeriana Di Castro, Aldo Venuti, Maria Rita Nicotra, Pier Giorgio Natali, Anna Bagnato
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 10 Pg. 2447-53 (May 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 12750265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Endothelial Growth Factors
• Endothelin Receptor Antagonists
• Growth Inhibitors
• Intercellular Signaling Peptides and Proteins
• Lymphokines
• Pyrrolidines
• Receptor, Endothelin A
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Paclitaxel
• Atrasentan

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Atrasentan
• Cell Division (drug effects)
• Drug Synergism
• Endothelial Growth Factors (biosynthesis)
• Endothelin Receptor Antagonists
• Female
• Growth Inhibitors (pharmacology)
• Humans
• Intercellular Signaling Peptides and Proteins (biosynthesis)
• Lymphokines (biosynthesis)
• Mice
• Mice, Nude
• Neovascularization, Pathologic (drug therapy)
• Ovarian Neoplasms (blood supply, drug therapy, pathology)
• Paclitaxel (administration & dosage)
• Pyrrolidines (administration & dosage, pharmacology)
• Receptor, Endothelin A
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Xenograft Model Antitumor Assays