The endothelin (ET) family consists of 3 peptides—ET-1, ET-2, and ET-3—each of which is composed of 21 amino acids. ETs are potent paracrine/autocrine factors with diverse activity, including modulation of vasomotor tone, nocioception, hormone production, cell proliferation, apoptosis, and stromal formation in a variety of tissues. These effects are predominantly mediated by the action of ET-1 on 2 G protein-coupled ET receptors: ETA and ETB.1,2 In 1993, ET-1 was shown to be produced by benign prostatic epithelial cells and, subsequently, by prostate cancer cells and to play a role in the pathophysiology of prostate cancer progression.3,4
Within the setting of prostate cancer, there is also an impairment of the ET-1 degradation pathway, resulting in a local increase in the concentration of ET-1.5 Furthermore, the expression of ETA receptors has been shown to be upregulated with prostate cancer tumor stage and grade.6 There are a number of pathways by which the ET-1/ETA axis may promote prostate cancer progression.4,7,8 ET-1 is mitogenic for prostate cancer cell lines in vitro and acts synergistically with other peptide growth factors.7 ET-1 is also a mitogen for osteoblasts, the cell type that is pivotal in the hallmark osteoblastic response of bone to metastatic prostate cancer.4,8 Selective ETA-receptor antagonists have been shown to block the proliferative effects of exogenous ET-1 in both prostate cancer cells and osteoblasts.7,9 This observation has generated a great deal of interest in ETAreceptor antagonists for the management of advanced prostate cancer. The following recently published article reports on this subject.
Effect of Endothelin-A Receptor Blockade With Atrasentan on Tumor Progression in Men With Hormone-Refractory Prostate Cancer: A Randomized, Phase II, Placebo-Controlled Trial
Carducci MA, Padley RJ, Breul J, et al.
J Clin Oncol. 2003;21:679–689.
Carducci and colleagues evaluated the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antago- nist, for the treatment of asymptomatic, hormone-refractory prostate adenocarcinoma (HRPCa) in a double-blind, randomized, placebo-controlled clinical trial conducted in the United States and Europe. A total of 288 asymptomatic men with HRPCa and evidence of metastatic disease were recruited into the study. The men were randomly assigned to a once-daily oral dose of one of the following: placebo; atrasentan, 2.5 mg; or atrasentan, 10 mg. The primary end point of the study was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers. Results demonstrated that, among the 244 evaluable men, the median time to progression was significantly prolonged in the atrasentan, 10 mg, group compared with the placebo group (196 vs 129 days; P < .03). Furthermore, the median time to PSA progression for the atrasentan, 10 mg, group was twice that of the placebo group (155 vs 71 days; P < .003). Men who received placebo continued to have significant increases from baseline in serum lactate dehydrogenase (LDH), a marker of disease burden, whereas elevations in LDH were uniformly attenuated by atrasentan (P < .01). Adverse events occurred in 16% to 34% of the men who received atrasentan, 10 mg. These events were usually mild to moderate in severity and included dyspnea, headache, rhinitis, and peripheral edema.
Although this study demonstrated that atrasentan, with favorable tolerability, delays progression of HRPCa, it failed to investigate the agent’s influence on survival. This important issue needs to be addressed in future phase III protocols. In addition, the investigators reported that quality of life was neither adversely affected nor improved by atrasentan. The wide use of atrasentan for the management of advanced prostate cancer awaits further clinical trials and results of survival and quality-of-life studies.
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