Endothelin receptor antagonists in cancer therapy.

Endothelins are a family of peptide compounds which exert regulatory control over cellular processes important for growth, survival, invasion, and angiogenesis. In particular, endothelin-1, acting primarily through the endothelin-A receptor, is implicated in the neoplastic growth of multiple tumor types. In preclinical models, endothelin antagonism inhibits tumor cell proliferation, invasiveness, and new vessel formation, as well as attenuates osteoblastic and pain-related responses to tumor. Clinical testing of an orally bioavailable endothelin antagonist has demonstrated benefit in PSA progression, markers of bone turnover, and pain in men with prostate cancer, but has not demonstrated significant improvement in survival or time to cancer progression. Although this class of drugs is promising for targeted anti-cancer therapy, their role in treatment remains to be defined by completion of future clinical trials.