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.
Rosanò
Laura
L
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Rome, Italy.
Spinella
Francesca
F
Di Castro
Valeriana
V
Natali
Pier Giorgio
PG
Bagnato
Anna
A
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077868:Atrasentan; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017239:Paclitaxel / Q000008:administration & dosage; D011759:Pyrrolidines / Q000008:administration & dosage; D044022:Receptor, Endothelin A / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D017239:Paclitaxel; D002945:Cisplatin; D000077868:Atrasentan