Endothelin-1 as a Target for Therapeutic Intervention in Prostate Cancer

The endothelins, a family of potentvasoconstricting peptides, have beenimplicated in the pathophysiology ofadvanced prostate cancer. Two endothelinreceptors, ET-A and ET-B are found innormal prostate tissue. Malignant prostatecells are notable for the loss of ET-Breceptors and increased levels ofendothelin-1 [ET-1]; this distortion of theendothelin system may be a significantfactor in the progression of prostatecancer. Proposed roles for endothelin inprostate cancer include growth promotion,apoptosis inhibition, bone formation, andstimulation of nociceptive receptors. ET-1can act alone as a mitogen, but its effectsare greatest as a comitogen with a varietyof growth factors, including basicfibroblast growth factor, insulin-likegrowth factors, and platelet derived growthfactor. Although their exact functions areunclear, ET-1, in conjunction with vascularendothelial growth factor, appears to playa major role in tumor angiogenesis. By avariety of methods, ET-1 alters the balanceof osteoblast and osteoclasts to the favornew bone formation that is characteristicof metastatic disease. Several studiesindicate that the refractory pain ofmetastatic cancer is related to the directnociceptive effects ET-1. These findingssuggest that ET receptors are promisingtherapeutic targets for pharmacologicintervention. Early clinical trialsindicate that the ET-A receptor antagonistused in prostate cancer is reasonably welltolerated with mild but pervasive symptomsrelated to ET-1's vasoconstrictive effects. Results of ongoing clinical trials areeagerly awaited in order to see if thehypothetical promise of ET antagonism willresult in clinical success.