title: Effects of steroidal and non-steroidal antiandrogens on wild-type and mutant androgen receptors.
abstract: BACKGROUND
  Molecular basis for secondary antiandrogen therapy in prostate cancer with mutant androgen receptors (ARs) is not fully elucidated.
  
  
  METHODS
  Effects of steroidal and non-steroidal antiandrogens on transcriptional activities of wild-type and mutant (W741C, T877A, and W741C+T877A) ARs were measured. Crystal structure analysis and docking studies were performed using Molecular Operating Environment (MOE) package.
  
  
  RESULTS
  DHT-induced transcriptional activity of the T877A mutant and the W741C mutant was suppressed by bicalutamide and hydroxyflutamide, respectively. Nilutamide suppressed the W741C mutant and the double mutant. Cyproterone acetate modestly inhibited the W741C mutant and the double mutant. The structural studies suggested that nilutamide and cyproterone acetate retain their antiandrogenic properties against both the W741C mutant and the double mutant due to fact that mutation W741C does not permit formation of key hydrophobic interaction between ligand and AR ligand binding domain, which is necessary for their conversion into agonists.
  
  
  CONCLUSIONS
  Switching antiandrogens may be reasonable in prostate cancer with mutant ARs.
authors: Department of Urology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Masayasu
authors: M
authors: Urushibara
authors: Junichiro
authors: J
authors: Ishioka
authors: Nobuhiko
authors: N
authors: Hyochi
authors: Kazunori
authors: K
authors: Kihara
authors: Shuntaro
authors: S
authors: Hara
authors: Pratap
authors: P
authors: Singh
authors: John T
authors: JT
authors: Isaacs
authors: Yukio
authors: Y
authors: Kageyama
mesh_terms: D000500:Allylestrenol / Q000494:pharmacology; D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D017373:Cyproterone Acetate / Q000737:chemistry / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D014105:Tosyl Compounds / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D048289:Imidazolidines; D009570:Nitriles; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C014290:hydroxyflutamide; D013739:Testosterone; D017373:Cyproterone Acetate; C021277:nilutamide; C013915:boldenone; D005485:Flutamide; C053541:bicalutamide; D017430:Prostate-Specific Antigen; D000500:Allylestrenol