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

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.