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

J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S132-5. doi: 10.1097/01.fjc.0000166259.96980.6a.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / prevention & control*
  • Paclitaxel / administration & dosage
  • Pyrrolidines / administration & dosage
  • Receptor, Endothelin A / metabolism
  • Time Factors
  • Xenograft Model Antitumor Assays

Substances

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