ZD4054: A Specific Endothelin A Receptor Antagonist with Promising Activity in Metastatic Castration-Resistant Prostate Cancer

摘要

Overexpression of the endothelin A (ẸTA) receptor has been found in a number of human cancer cell lines. Activation of the ETA receptor by endothelin-1 (ET-1) promotes cell proliferation and survival in these tumors, whereas activation of the endothelin B (ETB) receptor results in an opposing effect. Therefore, blockade of ETA may have antitumor effects, while sparing ETB-mediated effects such as induction of apoptosis and clearance of ET-1. ZD4054 is an orally bioavailable, specific ETA antagonist currently being investigated in prostate cancer. In receptor-binding studies, ZD4054 only bound to ETA with no binding detected towards ETB. Prostate cancer cell lines are known to produce ET-1 and there is a relative increase in expression of ETA to ETB in these cancers. There is also an association of greater ETA expression in higher grade versus lower grade tumors, suggesting that ETA may be involved in the malignant transformation process. Since ET-1 may also mediate nociceptive effects and osteoblastic effects, there is much interest in clinically assessing ZD4054 in prostate cancer.