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Drugs Fut 2009, 34(8): 624
ISSN 0377-8282
e-ISSN 2013-0368
Copyright 2009 Clarivate
CCC: 0377-8282
DOI: 10.1358/dof.2009.34.8.1400202
James, N.D., Growcott, J.W.
Endothelin-1 (ET-1) is a 21-amino-acid peptide factor that binds two receptors, ETA and ETB, which exert distinct biological effects. Zibotentan (ZD4054) is a specific ETA receptor antagonist in clinical development for the treatment of hormone-resistant prostate cancer (HRPC). In preclinical studies, zibotentan inhibited ET-1-mediated changes in cellular invasiveness in vitro, and inhibited angiogenesis, metastasis and the growth of tumor xenografts in vivo. Consistent with its specific binding profile, zibotentan inhibited ETA receptor-mediated antiapoptotic events, while allowing ETB receptor-mediated proapoptotic signaling. In the clinical setting, the absence of zibotentan activity at the ETB receptor was demonstrated by the stability of circulating ET-1 levels following single zibotentan doses up to 240 mg. In a randomized, placebo-controlled phase II trial in patients with pain-free or mildly symptomatic metastatic HRPC (N = 312), zibotentan was generally well tolerated, with an adverse effect profile consistent with its known pharmacological activity, the most common adverse events being headache, peripheral edema and nasal congestion. Although there was no significant difference between zibotentan treatment groups and placebo for the primary endpoint of time to progression, there was a promising signal for prolonged overall survival with zibotentan. These results support the strategy of targeting the ETA receptor in prostate cancer. Phase III trials are under way.

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