Androgen deprivation therapy for prostate cancer: Current status and future prospects

Androgens play a major role in promoting the development and progression of prostate cancer. As a result, androgen ablation or blockade of androgen action through the androgen receptor (AR) has been the cornerstone of treatment of advanced prostate cancer. Different strategies involving this hormonal therapy produce a significant clinical response in most of the patients, but most responders eventually lose dependency, resulting in mortality. Thus, whether hormonal therapy contributes to the improvement of overall survival rates, especially in patients with advanced prostate cancer, remains controversial. However, patients with advanced disease clearly have a benefit from androgen deprivation‐based treatment for palliating their symptoms and for improving the quality of their lives. In order to improve overall survival, novel treatment strategies that prolong the androgen‐dependent state and that are useful for androgen‐independent disease based on specific molecular mechanisms need to be identified. © 2004 Wiley‐Liss, Inc.

[1]  M. Resnick,et al.  A comparison of Zoladex® and DES in the treatment of advanced prostate cancer: Results of a randomized, multicenter trial , 1991, The Prostate.

[2]  Hong-Chiang Chang,et al.  A Dominant-negative Mutant of Androgen Receptor Coregulator ARA54 Inhibits Androgen Receptor-mediated Prostate Cancer Growth* , 2002, The Journal of Biological Chemistry.

[3]  E. Bergstralh,et al.  Role of early adjuvant hormonal therapy after radical prostatectomy for prostate cancer. , 2001, The Journal of urology.

[4]  M. Loda,et al.  Estrogen Receptor in Prostate Cancer , 2001 .

[5]  R. Wittes,et al.  A reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma. , 1985, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  D. Feldman,et al.  The development of androgen-independent prostate cancer , 2001, Nature Reviews Cancer.

[7]  S. Egawa,et al.  A pilot study of intermittent androgen ablation in advanced prostate cancer in Japanese men. , 2000, Japanese journal of clinical oncology.

[8]  R. Stege Potential side‐effects of endocrine treatment of long duration in prostate cancer , 2000, The Prostate. Supplement.

[9]  E. Castle,et al.  The role of soy phytoestrogens in prostate cancer. , 2002, The Urologic clinics of North America.

[10]  T. Ikonen,et al.  Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation. , 1994, Endocrinology.

[11]  E. Langley,et al.  Evidence for an Anti-parallel Orientation of the Ligand-activated Human Androgen Receptor Dimer (*) , 1995, The Journal of Biological Chemistry.

[12]  F. Koga,et al.  Effects of intravenous administration of high dose-diethylstilbestrol diphosphate on serum hormonal levels in patients with hormone-refractory prostate cancer. , 1999, Endocrine journal.

[13]  A. Hussain,et al.  Docetaxel followed by hormone therapy after failure of definitive treatments for clinically localized/locally advanced prostate cancer: preliminary results. , 2001, Seminars in oncology.

[14]  M. Costantini,et al.  Monotherapy with nilutamide, a pure nonsteroidal antiandrogen, in untreated patients with metastatic carcinoma of the prostate. The Italian Prostatic Cancer Project. , 1991, The Journal of urology.

[15]  A. Schally,et al.  Targeted cytotoxic analog of luteinizing hormone‐releasing hormone AN‐207 inhibits the growth of PC‐82 human prostate cancer in nude mice , 1999 .

[16]  A. Schally,et al.  Inhibition of PC-3 human androgen-independent prostate cancer and its metastases by cytotoxic somatostatin analogue AN-238. , 1999, Cancer research.

[17]  E. Small,et al.  The antiandrogen withdrawal syndrome. Experience in a large cohort of unselected patients with advanced prostate cancer , 1995, Cancer.

[18]  W. Walters,et al.  The effects of chronic high dose androgen or estrogen treatment on the human prostate [corrected] , 1996 .

[19]  J. Bailar,et al.  Carcinoma of the Prostate: Treatment Comparisons , 1967 .

[20]  A. Hsing Hormones and prostate cancer: what's next? , 2001, Epidemiologic reviews.

[21]  L. Nazareth,et al.  Activation of the Human Androgen Receptor through a Protein Kinase A Signaling Pathway* , 1996, The Journal of Biological Chemistry.

[22]  C. Glass,et al.  Co-activators and co-repressors in the integration of transcriptional responses. , 1998, Current opinion in cell biology.

[23]  J. Gustafsson,et al.  Orphan nuclear receptors--the first eight years. , 1996, Molecular endocrinology.

[24]  E. Keller,et al.  Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  T. Tammela,et al.  Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program. , 2002, The Journal of urology.

[26]  M. Benson,et al.  Gene activity during the early phase of androgen-stimulated rat prostate regrowth. , 1989, Cancer research.

[27]  G. Chodak,et al.  A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. , 1996, Urology.

[28]  J. Srigley,et al.  Pathologic Effects of Neoadjuvant Cyproterone Acetate on Nonneoplastic Prostate, Prostatic Intraepithelial Neoplasia, and Adenocarcinoma: A Detailed Analysis of Radical Prostatectomy Specimens From a Randomized Trial , 2002, The American journal of surgical pathology.

[29]  T. Tsujii,et al.  Stronger suppression of serum testosterone and FSH levels by a synthetic estrogen than by castration or an LH-RH agonist. , 1997, Endocrine journal.

[30]  C. Heinlein,et al.  Androgen receptor (AR) coregulators: an overview. , 2002, Endocrine reviews.

[31]  Tetsurou Matsumoto,et al.  Different expression of androgen receptor coactivators in human prostate. , 2001, Urology.

[32]  M. Menon,et al.  The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. , 2001, The Journal of urology.

[33]  P. Smith,et al.  Effect of stilboestrol and testosterone on the incorporation of 75selenomethionine by prostatic carcinoma cells. , 1988, British journal of urology.

[34]  F. Labrie,et al.  Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist. , 1987, The Journal of urology.

[35]  S. Tucker,et al.  Treatment of localized prostate cancer with intermittent triple androgen blockade: preliminary results in 110 consecutive patients. , 2001, The oncologist.

[36]  P. Kantoff,et al.  Chemotherapy for prostate cancer. , 2002, Urology.

[37]  W. Oh Secondary hormonal therapies in the treatment of prostate cancer. , 2002, Urology.

[38]  M. Gleave,et al.  Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model , 1996, The Journal of Steroid Biochemistry and Molecular Biology.

[39]  D. Gillatt,et al.  Medical or surgical orchidectomy: the patients' choice. , 1991, BMJ.

[40]  S. Yeh,et al.  Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Kaplan 5α-reductase inhibitors: what role should they play? , 2001 .

[42]  W. Walters,et al.  The effects of chronic high dose androgen or estrogen treatment on the human prostate [corrected]. , 1996, Journal of Clinical Endocrinology and Metabolism.

[43]  Schr,et al.  Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. , 1994, The American journal of pathology.

[44]  J. Isaacs,et al.  Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer , 1996, The Prostate.

[45]  I. Thompson,et al.  Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. , 1998, The New England journal of medicine.

[46]  G. Bubley,et al.  Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. , 1995, The New England journal of medicine.

[47]  S. Groshen,et al.  Her-2/neu expression in prostate cancer: high level of expression associated with exposure to hormone therapy and androgen independent disease. , 2001, The Journal of urology.

[48]  C. Chatelain,et al.  French multicentre trial comparing Casodex (ICI 176,334) monotherapy with castration plus nilutamide in metastatic prostate cancer: a preliminary report. , 1994, European urology.

[49]  Y. Chen,et al.  Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. , 2001, Carcinogenesis.

[50]  M. T. Abreu-Martin,et al.  Mitogen-Activated Protein Kinase Kinase Kinase 1 Activates Androgen Receptor-Dependent Transcription and Apoptosis in Prostate Cancer , 1999, Molecular and Cellular Biology.

[51]  M. Gleave,et al.  Is the flare phenomenon clinically significant? Commentary , 2001 .

[52]  C. Roehrborn,et al.  Prospective determination of the hormonal response after cessation of luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer. , 1999, Urology.

[53]  M. Gleave,et al.  Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. , 2001, The Journal of urology.

[54]  A. D'Amico Radiation and hormonal therapy for locally advanced and clinically localized prostate cancer. , 2001, Urology.

[55]  S. Goldenberg,et al.  Use of cyproterone acetate in prostate cancer. , 1991, The Urologic clinics of North America.

[56]  J. Isaacs Antagonistic effect of androgen on prostatic cell death , 1984 .

[57]  Liang Xia,et al.  Functional analysis of 44 mutant androgen receptors from human prostate cancer. , 2002, Cancer research.

[58]  J. Lloreta,et al.  Her-2/neu Expression in Prostate Cancer , 2004, Clinical Cancer Research.

[59]  H. Scher,et al.  Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. , 1993, The Journal of urology.

[60]  M. Gleave,et al.  Preoperative neoadjuvant androgen withdrawal therapy in prostate cancer: the Canadian experience. , 2002, Urology.

[61]  B. Aggarwal,et al.  Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines , 2001, Oncogene.

[62]  W. Stadler,et al.  Nilutamide: possible utility as a second-line hormonal agent. , 2001, Urology.

[63]  D. Budman,et al.  Phosphorylation/dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity. , 1999, Biochemical and biophysical research communications.

[64]  M. Kattan,et al.  Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. , 1999, The Journal of urology.

[65]  R. Sylvester,et al.  Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). EORTC GU Group and EORTC Data Center. , 1993, Urology.

[66]  S. Yeh,et al.  Reducing the Agonist Activity of Antiandrogens by a Dominant-negative Androgen Receptor Coregulator ARA70 in Prostate Cancer Cells* , 2003, Journal of Biological Chemistry.

[67]  G. Wilding,et al.  Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[68]  M. Chen,et al.  Aberrant response in vitro of hormone‐responsive prostate cancer cells to antiandrogens , 1989, The Prostate.

[69]  K. Makino,et al.  HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. , 2000, Cancer research.

[70]  Miguel Beato,et al.  Steroid hormone receptors: Many Actors in search of a plot , 1995, Cell.

[71]  J. D. Wilson,et al.  Steroid 5 alpha-reductase: two genes/two enzymes. , 1994, Annual review of biochemistry.

[72]  J. Hugosson,et al.  Three‐month neoadjuvant hormonal therapy before radical prostatectomy: a 7‐year follow‐up of a randomized controlled trial , 2002, BJU international.

[73]  H. Gronemeyer,et al.  Activation Function 2 in the Human Androgen Receptor Ligand Binding Domain Mediates Interdomain Communication with the NH2-terminal Domain* , 1999, The Journal of Biological Chemistry.

[74]  Hong-Chiang Chang,et al.  Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator. , 2003, Cancer research.

[75]  Chawnshang Chang,et al.  Phosphorylation‐dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase , 2002, The EMBO journal.

[76]  M. Orlando,et al.  Low-dose continuous oral fosfestrol is highly active in 'hormone-refractory' prostate cancer. , 2000, Annals of oncology : official journal of the European Society for Medical Oncology.

[77]  M. Blankenstein,et al.  Effect of culture conditions on androgen sensitivity of the human prostatic cancer cell line LNCaP , 1993, The Prostate.

[78]  F. Labrie,et al.  Down-staging of early stage prostate cancer before radical prostatectomy: The first randomized trial of neoadjuvant combination therapy with flutamide and a luteinizing hormone-releasing hormone agonist , 1994 .

[79]  J C Reed,et al.  Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. , 1999, Science.

[80]  Crawford,et al.  Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials , 2000, The Lancet.

[81]  Y. Kubota,et al.  Fluorescence in situ hybridization evaluation of c‐myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients , 2000, The Prostate.

[82]  J. Isaacs,et al.  The biology of hormone refractory prostate cancer. Why does it develop? , 1999, The Urologic clinics of North America.

[83]  E. Small,et al.  Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. , 1999, Cancer research.

[84]  G. Jenster,et al.  Identification of Two Transcription Activation Units in the N-terminal Domain of the Human Androgen Receptor (*) , 1995, The Journal of Biological Chemistry.

[85]  C. Huggins,et al.  Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate , 1941, CA: a cancer journal for clinicians.

[86]  R L Vessella,et al.  Advances in Brief Amplification and Overexpression of Androgen Receptor Gene in Hormone-Refractory Prostate Cancer 1 , 2001 .

[87]  V. Reuter,et al.  HER‐2 profiling and targeting in prostate carcinoma , 2002, Cancer.

[88]  O. P. Luzardo,et al.  Transition to androgen-independence in prostate cancer , 2002, The Journal of Steroid Biochemistry and Molecular Biology.

[89]  H. Scher,et al.  Steroid hormone withdrawal syndromes. Pathophysiology and clinical significance. , 1997, The Urologic clinics of North America.

[90]  T. Ikonen,et al.  Interaction between the Amino- and Carboxyl-terminal Regions of the Rat Androgen Receptor Modulates Transcriptional Activity and Is Influenced by Nuclear Receptor Coactivators* , 1997, The Journal of Biological Chemistry.

[91]  Alicia Samuels,et al.  Cancer Statistics, 2003 , 2003, CA: a cancer journal for clinicians.

[92]  E. Gelmann,et al.  Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. , 2000, Cancer research.

[93]  G. Jenster Coactivators and corepressors as mediators of nuclear receptor function: An update , 1998, Molecular and Cellular Endocrinology.

[94]  D. Williams,et al.  The effects of diethylstilboestrol and castration on the nucleic acid and protein metabolism of rat prostate gland. , 1967, The Biochemical journal.

[95]  J. Kokontis,et al.  Identification of a new member of the steroid receptor super-family by cloning and sequence analysis. , 1988, Biochemical and biophysical research communications.

[96]  T. Tammela,et al.  A Randomised Comparison of ‘Casodex’TM (Bicalutamide) 150 mg Monotherapy versus Castration in the Treatment of Metastatic and Locally Advanced Prostate Cancer , 1998, European Urology.

[97]  W. Walters,et al.  Androgen or estrogen effects on human prostate , 1996 .

[98]  C. Mitsiades,et al.  A combination therapy of dexamethasone and somatostatin analog reintroduces objective clinical responses to LHRH analog in androgen ablation-refractory prostate cancer patients. , 2001, The Journal of clinical endocrinology and metabolism.

[99]  E. Crawford,et al.  Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. , 1993, The Journal of urology.

[100]  S. Malkowicz The role of diethylstilbestrol in the treatment of prostate cancer. , 2001, Urology.

[101]  J. Montie,et al.  Effectiveness of castration versus intravenous estrogen therapy in producing rapid endocrine control of metastatic cancer of the prostate. , 1985, The Journal of urology.

[102]  J. Geller Rationale for blockade of adrenal as well as testicular androgens in the treatment of advanced prostate cancer. , 1985, Seminars in oncology.

[103]  Mcleod,et al.  Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer. , 1997, The oncologist.

[104]  L. Klotz,et al.  Intermittent endocrine therapy for advanced prostate cancer , 1986, Cancer.

[105]  M. Holdsworth,et al.  Nilutamide: An Antiandrogen for the Treatment of Prostate Cancer , 1997, The Annals of pharmacotherapy.

[106]  Jacques Bernier,et al.  Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial , 2002, The Lancet.

[107]  F. S. French,et al.  A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. , 2001, Cancer research.

[108]  H. Perlman,et al.  Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. , 1995, Cancer research.

[109]  R. Mazess,et al.  Phase I trial of 1α-hydroxyvitamin D2 in patients with hormone refractory prostate cancer , 2002 .

[110]  F. Burkhard,et al.  Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? , 2003, The Journal of urology.

[111]  Chawnshang Chang,et al.  Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[112]  P. Cangh,et al.  Endocrine profiles during administration of the new non‐steroidal anti‐androgen Casodex in prostate cancer , 1994, Clinical endocrinology.

[113]  M. Oefelein Health related quality of life using serum testosterone as the trigger to re-dose long acting depot luteinizing hormone-releasing hormone agonists in patients with prostate cancer. , 2003, The Journal of urology.

[114]  E. Wilson,et al.  Hormone-dependent Transactivation by the Human Androgen Receptor Is Regulated by a dnaJ Protein (*) , 1995, The Journal of Biological Chemistry.

[115]  M. Campbell,et al.  Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. , 1992, Cancer research.

[116]  D. Byar,et al.  Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. , 1989, NCI monographs : a publication of the National Cancer Institute.

[117]  G. Buchanan,et al.  Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[118]  P. Abrahamsson Neuroendocrine differentiation in prostatic carcinoma , 1999, The Prostate.

[119]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.

[120]  Benjamin R. Lee,et al.  Comparison of robotic versus laparoscopic skills: is there a difference in the learning curve? , 2002, Urology.

[121]  S. Berger Gene activation by histone and factor acetyltransferases. , 1999, Current opinion in cell biology.

[122]  E. Crawford,et al.  Treatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. , 1998, Urology.

[123]  K. Bemis,et al.  Kinetic analysis of LY320236: competitive inhibitor of type I and non-competitive inhibitor of type II human steroid 5α-reductase , 2000, The Journal of Steroid Biochemistry and Molecular Biology.

[124]  S. Balk,et al.  Androgen receptor as a target in androgen-independent prostate cancer. , 2002, Urology.

[125]  D. McDonnell,et al.  Evaluation of ligand-dependent changes in AR structure using peptide probes. , 2002, Molecular endocrinology.

[126]  S. Yeh,et al.  From estrogen to androgen receptor: a new pathway for sex hormones in prostate. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[127]  D. Kuban,et al.  Impact of androgen deprivation therapy on survival in men treated with radiation for prostate cancer. , 2002, Urology.

[128]  G. Bubley,et al.  Is the flare phenomenon clinically significant? , 2001, Urology.

[129]  G. Hanks,et al.  Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. , 2001, International journal of radiation oncology, biology, physics.

[130]  N. Webster,et al.  The human estrogen receptor has two independent nonacidic transcriptional activation functions , 1989, Cell.

[131]  D. Ornstein,et al.  Biochemical response to testicular androgen ablation among patients with prostate cancer for whom flutamide and/or finasteride therapy failed. , 1998, Urology.

[132]  H. Chang,et al.  Antiandrogens fail to block androstenedione‐mediated mutated androgen receptor transactivation in human prostate cancer cells , 2000, International journal of urology : official journal of the Japanese Urological Association.

[133]  D. Newling,et al.  Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer. , 2001, Urology.

[134]  P. Ditonno,et al.  Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: results of an Italian Prostate Cancer Project study. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[135]  Y. Furuya,et al.  Response of Prostate-Specific Antigen after Androgen Withdrawal and Prognosis in Men with Metastatic Prostate Cancer , 1998, Urologia Internationalis.

[136]  S. Goldenberg,et al.  Effects of intermittent androgen suppression on androgen‐dependent tumors. Apoptosis and serum prostate‐specific antigen , 1993, Cancer.

[137]  E. Messing,et al.  Activation of mitogen-activated protein kinase pathway by the antiandrogen hydroxyflutamide in androgen receptor-negative prostate cancer cells. , 2002, Cancer research.

[138]  H. Stricker,et al.  Luteinizing hormone-releasing hormone antagonists in prostate cancer. , 2001, Urology.

[139]  D. Grignon,et al.  Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. , 2001, International journal of radiation oncology, biology, physics.

[140]  D. Budman,et al.  Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines. , 1997, British journal of urology.

[141]  D. Wood,et al.  Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. , 2002, The Journal of urology.

[142]  K. Akakura,et al.  Codon 877 Mutation in the Androgen Receptor Gene in Advanced Prostate Cancer: Relation to Antiandrogen Withdrawal Syndrome , 1996, The Prostate.

[143]  P. Stricker,et al.  Growth factor involvement in progression of prostate cancer. , 1998, Clinical chemistry.

[144]  M. Gleave,et al.  Intermittent androgen suppression in prostate cancer: the Canadian experience. , 2002, Urology.

[145]  P. Iversen Antiandrogen monotherapy: indications and results. , 2002, Urology.

[146]  M. Bishop Experience with low-dose oestrogen in the treatment of advanced prostate cancer: a personal view. , 1996, British journal of urology.

[147]  E. Horwitz,et al.  Subset analysis of RTOG 85-31 and 86-10 indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy. , 2001, International journal of radiation oncology, biology, physics.

[148]  H. Klocker,et al.  Androgen receptor – an update of mechanisms of action in prostate cancer , 2000, Urological Research.

[149]  Chawnshang Chang,et al.  Molecular cloning of human and rat complementary DNA encoding androgen receptors. , 1988, Science.

[150]  G. Jenster,et al.  A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. , 1990, Biochemical and biophysical research communications.

[151]  C. Huggins,et al.  Bilateral Adrenalectomy in Prostatic Cancer: Clinical Features and Urinary Excretion of 17-Ketosteroids and Estrogen. , 1945, Annals of surgery.

[152]  J. Manola,et al.  Immediate hormonal therapy versus observation after radical prostatectomy and pelvic lymphadenectomy for node positive prostate cancer: At 10 years results of EST3886. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[153]  E. Messing,et al.  Δ5-Androstenediol is a natural hormone with androgenic activity in human prostate cancer cells , 1998 .

[154]  N. Kyprianou,et al.  Relationship between DNA fragmentation and apoptosis in the programmed cell death in the rat prostate following castration , 1989, The Prostate.

[155]  A. Shabsigh,et al.  The effects of androgen deprivation on the prostate gland: cell death mediated by vascular regression , 2000, Current opinion in urology.

[156]  H. Klocker,et al.  Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor and epidermal growth factor. , 1995, European urology.

[157]  W. von Rechenberg,et al.  Pharmacological Studies on Androgen Suppression in Therapy of Prostate Carcinoma , 1988, American journal of clinical oncology.

[158]  J. Crook,et al.  Intermittent androgen suppression in the management of prostate cancer. , 1999, Urology.

[159]  W P Sheridan,et al.  Development of GnRH antagonists for prostate cancer: new approaches to treatment. , 2000, The oncologist.

[160]  G. Prins,et al.  Androgen receptor localization in different cell types of the adult rat prostate. , 1991, Endocrinology.

[161]  T. Wilt,et al.  Combined androgen blockade with nonsteroidal antiandrogens for advanced prostate cancer: a systematic review. , 2001, Urology.

[162]  M. Motta,et al.  Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145: evidence for an autocrine-inhibitory LHRH loop. , 1994, Cancer research.

[163]  R. Yates,et al.  Metabolism and enantioselective pharmacokinetics of Casodex in man. , 1993, Xenobiotica; the fate of foreign compounds in biological systems.

[164]  M. Ziveri,et al.  Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer. The Italian Prostatic Cancer Project (PONCAP) Study Group. , 1993, European journal of cancer.

[165]  J. Manola,et al.  Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. , 1999, The New England journal of medicine.

[166]  C. Ashton,et al.  Living with treatment decisions: regrets and quality of life among men treated for metastatic prostate cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[167]  Jerome Seidenfeld,et al.  Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer , 2000, Annals of Internal Medicine.

[168]  H. Klocker,et al.  Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. , 1993, Molecular endocrinology.

[169]  V. Ogryzko,et al.  p300 and p300/cAMP-response Element-binding Protein-associated Factor Acetylate the Androgen Receptor at Sites Governing Hormone-dependent Transactivation* , 2000, The Journal of Biological Chemistry.

[170]  W. Lee,et al.  The role of androgen deprivation therapy combined with prostate brachytherapy. , 2002, Urology.

[171]  G. Kolvenbag,et al.  Bicalutamide dosages used in the treatment of prostate cancer , 1999, The Prostate.

[172]  U. Tunn,et al.  Comparison of LH-RH Analogue 1-Month Depot and 3-Month Depot by Their Hormone Levels and Pharmacokinetic Profile in Patients with Advanced Prostate Cancer , 1998, Urologia Internationalis.

[173]  S. Yeh,et al.  Suppression of Delta(5)-androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[174]  L. Denis European Organization for Research and Treatment of Cancer (EORTC) prostate cancer trials, 1976-1996. , 1998, Urology.

[175]  J. Simard,et al.  History of LHRH agonist and combination therapy in prostate cancer , 1996 .

[176]  H. J. Voogt The position of cyproterone acetate (CPA), a steroidal anti-androgen, in the treatment of prostate cancer. , 1992 .

[177]  J. Eastham,et al.  Androgen receptor mutations in prostate cancer. , 2000, Cancer research.

[178]  R. Lieberman Androgen deprivation therapy for prostate cancer chemoprevention: current status and future directions for agent development. , 2001, Urology.

[179]  S. Yeh,et al.  Hydroxyflutamide may not always be a pure antiandrogen , 1997, The Lancet.

[180]  R. Evans,et al.  The steroid and thyroid hormone receptor superfamily. , 1988, Science.

[181]  F. Labrie,et al.  Androgen blockade in prostate cancer , 2000, The Lancet.

[182]  C. Cordon-Cardo,et al.  Response of prostate cancer to anti-Her-2/neu antibody in androgen-dependent and -independent human xenograft models. , 1999, Cancer research.

[183]  T. Tammela,et al.  Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. , 2000, The Journal of urology.

[184]  J. Lees,et al.  Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. , 1992, The EMBO journal.

[185]  B. Yeap,et al.  Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[186]  R. Buttyan,et al.  Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo , 2001, The Prostate.

[187]  John Trachtenberg,et al.  A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. , 2002, The Journal of urology.

[188]  G. Murphy,et al.  Circulating levels of interleukin‐6 in patients with hormone refractory prostate cancer , 1999, The Prostate.

[189]  O. Cussenot,et al.  Evaluation of androgen, estrogen (ER alpha and ER beta), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. , 2001, Cancer research.

[190]  P. Troncoso,et al.  Neoadjuvant chemotherapy and hormonal therapy followed by radical prostatectomy: feasibility and preliminary results. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[191]  D. Byar The veterans administration cooperative urological research group's studies of cancer of the prostate , 1973, Cancer.

[192]  M. Blute,et al.  Chemoprevention for prostatic carcinoma: The role of flutamide in patients with prostatic intraepithelial neoplasia. , 2001, Urology.

[193]  R. Lanz,et al.  Nuclear receptor coregulators: cellular and molecular biology. , 1999, Endocrine reviews.

[194]  R. Sylvester,et al.  The final analysis of the EORTC Genito-Urinary Tract Cancer Co-Operative Group phase III clinical trial (protocol 30805) comparing orchidectomy, orchidectomy plus cyproterone acetate and low dose stilboestrol in the management of metastatic carcinoma of the prostate. , 1995, European urology.

[195]  S. Ho,et al.  Expression of estrogen receptor (ER)-alpha and ER-beta in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation. , 2000, Cancer research.

[196]  F. Boccardo Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy? , 2000, Critical reviews in oncology/hematology.

[197]  J Isola,et al.  Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. , 1997, Cancer research.

[198]  E. Messing,et al.  Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[199]  M. Jones,et al.  A phase III open randomized study of Zoladex 3.6 mg depot vs. DES 3 mg per day in untreated advanced prostate cancer: a West Midlands Urological Research Group Study. , 1989, Progress in clinical and biological research.

[200]  D. Tindall,et al.  Androgen receptor signaling in androgen-refractory prostate cancer. , 2001, Journal of the National Cancer Institute.

[201]  M. Gleave,et al.  Neoadjuvant androgen withdrawal therapy decreases local recurrence rates following tumor excision in the Shionogi tumor model. , 1997, The Journal of urology.

[202]  R. Fine,et al.  Induction of apoptosis by diethylstilbestrol in hormone-insensitive prostate cancer cells. , 1996, Journal of the National Cancer Institute.

[203]  Chawnshang Chang,et al.  3β-Acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[204]  W. Ellis,et al.  Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. , 1996, Urology.

[205]  Michael M Lieber,et al.  The influence of finasteride on the development of prostate cancer. , 2003, The New England journal of medicine.

[206]  D. Gleason,et al.  A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. , 2001, Urology.

[207]  S. Fosså,et al.  Assessment of quality of life in patients with prostate cancer. , 1994, Seminars in oncology.

[208]  J. Trapman,et al.  Mechanisms of androgen receptor activation and function , 1999, The Journal of Steroid Biochemistry and Molecular Biology.

[209]  S. Suciu,et al.  Cardiovascular side effects of diethylstilbestrol, cyproterone acetate, medroxyprogesterone acetate and estramustine phosphate used for the treatment of advanced prostatic cancer: results from European Organization for Research on Treatment of Cancer trials 30761 and 30762. , 1986, The Journal of urology.

[210]  S. Inui,et al.  Cloning and Characterization of Androgen Receptor Coactivator, ARA55, in Human Prostate* , 1999, The Journal of Biological Chemistry.

[211]  S. Venitt,et al.  Detection of telomerase activity in human prostate: a diagnostic marker for prostatic cancer? , 1997, British journal of urology.

[212]  M. Bosland The role of steroid hormones in prostate carcinogenesis. , 2000, Journal of the National Cancer Institute. Monographs.

[213]  J. Isaacs,et al.  Role of calcium in the programmed death of rat prostatic glandular cells , 1990, The Prostate.

[214]  Bruce Gottlieb,et al.  The androgen receptor gene mutations database , 1996, Nucleic Acids Res..

[215]  K. Delaere,et al.  Flutamide monotherapy as primary treatment in advanced prostatic carcinoma. , 1991, Seminars in oncology.

[216]  A. Saltzman,et al.  Androgen receptor: an overview. , 1995, Critical reviews in eukaryotic gene expression.

[217]  F. Labrie,et al.  Benefits of combination therapy with flutamide in patients relapsing after castration. , 1988, British journal of urology.

[218]  P. Goodman,et al.  A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. , 1989, The New England journal of medicine.

[219]  B. Katchen,et al.  Disposition of a New, Nonsteroid, Antiandrogen, α,α,α-Trifluoro-2-methyl-4′-nitro-m-propionotoluidide (Flutamide), in Men Following a single Oral 200 mg Dose , 1975 .

[220]  P. Boyle,et al.  Finasteride in association with either flutamide or goserelin as combination hormonal therapy in patients with stage M1 carcinoma of the prostate gland , 1999, The Prostate.

[221]  P. Iversen,et al.  Gynecomastia in patients with prostate cancer: a review of treatment options. , 2000, Urology.

[222]  Chawnshang Chang,et al.  Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily , 2002, The Journal of Steroid Biochemistry and Molecular Biology.