Send Orders for Reprints to reprints@benthamscience.net Clinical Immunology, Endocrine & Metabolic Drugs, 2014, 1, 11-19 11 Androgen Receptor Antagonists in the Treatment of Prostate Cancer Takashi Kawahara and Hiroshi Miyamoto * Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Abstract: Antiandrogens that block androgen action through the androgen receptor, often in conjunction with chemical or surgical castration, have been widely used for the treatment of advanced prostate cancer. Although this treatment produces a significant clinical response in most of the patients, the majority of the responders eventually develop recurrences termed castration-resistant prostate cancer. In addition, clinically available androgen receptor antagonists have been shown to possess agonist activity, resulting in an increase in serum prostate-specific antigen levels, which is known as the antiandrogen withdrawal syndrome. Recent studies have demonstrated that new types of androgen receptor signaling in- hibitors improve survival in men with castration-resistant prostate cancer. Moreover, other drugs may have the potential of not inducing androgen withdrawal response. This article reviews the characteristics of classical and recent androgen re- ceptor antagonists as well as their clinical efficacy in prostate cancer patients. Novel experimental compounds that may more specifically and effectively target androgens and/or androgen receptor signals in hormone-naive and possibly castra- tion-resistant prostate cancer cells are also discussed. Keywords: Androgen, androgen receptor, antiandrogen, castration, combined androgen blockade, cytochrome P450-17, hormonal therapy, prostate cancer. INTRODUCTION Prostate cancer is one of the most common causes of malignancy and cancer death among men worldwide [1]. Since the first report in 1941 [2], androgen deprivation ther- apy has contributed to the management of almost every stage of prostate cancer [3-7]. Hormonal manipulation in men with prostate cancer can be achieved by reduction in the availabil- ity of androgens and/or interference with their functions through the androgen receptor (AR) pathway. Thus, antian- drogens are often used in conjunction with castration as combined androgen blockade (CAB). However, after a brief clinical response, most of the responders ultimately develop hormone-refractory tumors known as castration-resistant prostate cancer (CRPC). Emerging evidence showing AR activation is often associated with its overexpression in CRPC [3-7] suggesting that hormone-refractory tumors re- main AR-dependent for their growth. Accordingly, therapeu- tic options, including not only cytotoxic agents such as do- cetaxel but also novel AR signaling inhibitors, have been evaluated in patients with CRPC [8, 9]. In addition, classical antiandrogens that competitively inhibit binding of andro- gens to the AR in target cells have been reported to raise the levels of prostate-specific antigen (PSA), an AR-responsive gene, during CAB [10]. This phenomenon is known as antiandrogen withdrawal syndrome (AWS), and a subset of patients benefit from the withdrawal of antiandrogens. This article aims to provide clinical and molecular *Address correspondence to this author at the James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287, USA; Tel: +1(410)614-1442; Fax: +1(410)955- 0833; E-mail: hmiyamo1@jhmi.edu evidence supporting the efficacy of classical and new AR antagonists in prostate cancer as well as its controversies. STEROIDAL ANTIANDROGENIC DRUGS Steroidal antiandrogens do not only compete with androgens for the binding to the AR but also contribute to a decrease in plasma levels of testosterone and 5α-dihydrotestosterone (DHT) by slowing the release of pituitary leutenizing hor- mone (LH) and by partial inhibition of 5α-reductase [4, 11]. Thus, steroidal antiandrogens, as single agents, may yield CAB. There are a few steroidal antiandrogens, including cyproterone acetate (CPA), megestrol acetate (MGA), and chlormadinone acetate (CMA), which have been clinically used for the treatment of prostate cancer as monotherapy or in combination with castration. CPA CPA was first reported in 1967 as a steroidal antiandro- genic agent that inhibited the action of adrenal and testicular androgens in prostatic cells [12]. It also possesses progesto- genic activity, leading to a centrally mediated reduction in testicular secretion of androgens [13]. In earlier clinical stud- ies of prostate cancer, there were no significant differences in disease-specific survival between CPA monotherapy and any other forms of androgen ablation, including surgical castration, LH-releasing hormone (LH-RH) agonists, and non-steroidal androgens [14]. In a more recent randomized clinical trial involving 310 men with metastatic prostate can- cer, CPA monotherapy was again shown to have similar effi- cacy in disease progression and survival to a non-steroidal antiandrogen flutamide monotherapy [15]. A collaborative 2212-7089/14 $58.00+.00 © 2014 Bentham Science Publishers