Therapeutic targeting of the endothelin-A receptor in human ovarian carcinoma: efficacy of cytotoxic agents is markedly enhanced by co-administration with atrasentan.

Abstract

The endothelin-1/endothelin-A receptor autocrine pathway is overexpressed in ovarian carcinoma. We explored the efficacy of atrasentan (ABT-627), a small orally active endothelin- A receptor antagonist, in monotherapy and combination therapy on HEY ovarian carcinoma xenografts. Atrasentan (2 mg/kg per 24 hours i.p. for 21 days) induced similar inhibition of tumor growth as paclitaxel (20 mg/kg i.v. three times a day every 4 days) with a reduction of 65% compared to control. The co-administration of atrasentan enhanced the efficacy of cytotoxic agents, such as taxanes or platinum compounds. Administration of atrasentan in combination with paclitaxel caused a strong antitumor effect. Remarkably, four of ten mice bearing HEY xenografts had no histological evidence of tumors. Tumor growth inhibition was accompanied by a significant decrease of molecular effectors involved in angiogenesis and invasion and by enhanced tumor cell apoptosis. Moreover, although cisplatinum as a single agent (5 mg/kg i.p. on day 1) markedly inhibited HEY tumors, atrasentan was very effective in potentiating this effect, with partial or complete tumor regression. The antitumor, anti-angiogenic, and apoptotic activities obtained with atrasentan and the enhanced efficacy of cytotoxic agents provide a rationale for its clinical evaluation in ovarian carcinoma.

• Authors: Laura Rosanò, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Anna Bagnato
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 44 Suppl 1 Pg. S132-5 (Nov 2004) ISSN: 1533-4023 [Electronic] United States
• PMID: 15838262 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents, Phytogenic
• Endothelin A Receptor Antagonists
• Pyrrolidines
• Receptor, Endothelin A
• Paclitaxel
• Cisplatin
• Atrasentan

Topics

• Angiogenesis Inhibitors (administration & dosage)
• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Atrasentan
• Cell Line, Tumor
• Cisplatin (administration & dosage)
• Endothelin A Receptor Antagonists
• Female
• Humans
• Injections, Intraperitoneal
• Injections, Intravenous
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Neovascularization, Pathologic (prevention & control)
• Ovarian Neoplasms (blood supply, metabolism, pathology, prevention & control)
• Paclitaxel (administration & dosage)
• Pyrrolidines (administration & dosage)
• Receptor, Endothelin A (metabolism)
• Time Factors
• Xenograft Model Antitumor Assays