The Role of Endothelin in Hormone-Refractory Prostate Cancer

Abstract

Aggressive chemotherapy has made only a limited contribution to improvements in patient prognosis and well-being in hormone-refractory prostate cancer (HRPC). Such poor progress results from the biological basis of the disease, localisation of the tumour and the relatively high age of affected men, and leaves patients with a dismal prognosis. Given the palliative role of current treatments, attention has focused on the development of therapies targeted at non-androgenic mediators of prostate growth. Endothelin-1 (ET-1), a 21-amino-acid peptide produced by endothelial cells and prevalent in seminal fluid, has been identified as one such mediator. In addition to its potent mitogenic and vasoconstrictive properties, ET-1 has been shown to suppress apoptosis and induce angiogenesis. In HRPC cells, increased levels of ET-1 have been observed. ET-1 mediates its effects through two receptors, of which the endothelin-A (ET A) receptor is most important in prostate cancer. An up-regulation of ET A receptor levels and decreased expression of endothelin-B (ET B) receptors is observed in HRPC cells. Taken together, these factors are thought to play a significant role in the progression of the disease. Research has, therefore, focused on development of ET-1 antagonists to disrupt the mitogenic and angiogenic effects of ET-1 and slow disease progression. As ET-1 is also an important factor in the development of new bone, ET-1 antagonists may potentially inhibit the development of skeletal metastases and associated pain, which characterise this disease. Atrasentan, a highly specific ET A receptor antagonist, is currently in clinical development. Data are awaited from clinical trials to confirm the role of this agent in the treatment of HRPC.