Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Abstract

The endothelin A receptor (ETAR) autocrine pathway is overexpressed in many malignancies, including nasopharyngeal carcinoma (NPC). In this tumor, ETAR expression is an independent determinant of survival and a robust independent predictor of distant metastasis. To evaluate whether ETAR represents a new target in NPC treatment, we tested the therapeutic role of ETAR in NPC. Cell proliferation was inhibited by the ETAR-selective antagonist ABT-627 in two ETAR-positive NPC cells in a dose-dependent manner. Proliferation of ETAR-negative NPC cells was not decreased. ETAR blockade also resulted in sensitization to cisplatin and 5-fluorouracil-induced apoptosis. In nude mice, ABT-627 inhibited the growth of NPC cell xenografts. Combined treatment of ABT-627 with the cytotoxic drug cisplatin or 5-fluorouracil produced additive antitumor effects. The antitumor activity of ABT-627 was demonstrated finally on an experimental lung metastasis by a reduction in the number of tumors. These results support the rationale of combining ABT-627 with current standard chemotherapy to further improve the therapeutic ratio in the treatment of NPC. © 2006 Japanese Cancer Association.