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[Cancer Research 63, 2447-2453, May 15, 2003]
© 2003 American Association for Cancer Research

Experimental Therapeutics

Therapeutic Targeting of the Endothelin A Receptor in Human Ovarian Carcinoma1

Laura Rosanò, Francesca Spinella, Debora Salani, Valeriana Di Castro, Aldo Venuti, Maria Rita Nicotra, Pier Giorgio Natali and Anna Bagnato2

Laboratories of Molecular Pathology and Ultrastructure [L. R., F. S., D. S., V. D. C., A. B.], Immunology [P. G. N.], and Virology [A. V.], Regina Elena Cancer Institute, 00158 Rome, Italy, and Biotechnology Department, Consiglio Nazionale delle Ricerche [M. R. N.], 00137 Rome, Italy

The endothelin A receptor (ETAR) autocrine pathway is overexpressed in many malignancies, including ovarian carcinoma. In this tumor, engagement of ETAR triggers tumor growth, survival, neoangiogenesis, and invasion. To evaluate whether ETAR represents a new target in cancer treatment, we examine in vitro and in vivo the effect of the selective ETAR 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. ETAR blockade also results in the sensitization to paclitaxel-induced apoptosis. In ovarian carcinoma xenografts, in which the ET-1/ETAR 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 ETAR signaling therefore, represents, a promising therapeutic strategy in ovarian carcinoma.




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Cancer Research Clinical Cancer Research
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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2003 by the American Association for Cancer Research.