title: Testosterone boosts for treatment of castration resistant prostate cancer: an experimental implementation of intermittent androgen deprivation.
abstract: BACKGROUND
  The primary therapeutic target for non-organ-confined prostate cancer is the androgen receptor (AR). Main strategies to ablate AR function are androgen depletion and direct receptor blockade by AR antagonists. However, incurable castration resistant prostate cancer (CRPC) develops resistance mechanisms to cope with trace amounts of androgen including AR overexpression and mutation in the AR ligand binding domain.
  
  
  METHODS
  The CRPC cell model VCaP derivative of a prostate cancer bone metastasis was used in vitro and in nude mice in vivo to examine the effects of immediate testosterone boost on CRPC cells. In addition, a testosterone tolerant cell model was established by incremental acclimatization of VCaP cells to 1 nM testosterone. The effects of androgen withdrawal and testosterone boosts on gene expression were assessed by quantitative real-time polymerase chain reaction, ELISA, and Western blots. Tumor cell proliferation was evaluated with a BrdU test.
  
  
  RESULTS
  Testosterone boosts on CRPC VCaP cells eliminate tumor cells to a higher extent than androgen withdrawal in androgen tolerant cells. The pronounced decrease of tumor cell proliferation was accompanied by a marked downregulation of AR expression regarding full-length AR and splice variant AR V7.
  
  
  CONCLUSIONS
  Acquiring castration resistance of prostate cancer cells by AR overexpression and amplification obviously sensitizes such cells to testosterone concentrations as low as physiological values. This introduces novel therapeutic means to treat CRPC with non-toxic measures and may find clinical implementation in intermittent androgen deprivation regimens.
authors.affiliation: Department of Urology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Thelen
authors.forename: Elmar
authors.initials: E
authors.lastname: Heinrich
authors.forename: Felix
authors.initials: F
authors.lastname: Bremmer
authors.forename: Lutz
authors.initials: L
authors.lastname: Trojan
authors.forename: Arne
authors.initials: A
authors.lastname: Strauss
mesh_terms: D000728:Androgens / Q000172:deficiency*; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary / Q000601:surgery; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000627:therapeutic use*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D013739:Testosterone
keywords: androgen receptor; castration resistant prostate cancer (CRPC); intermittent androgen deprivation (IAD); resistance mechanisms; therapy resistance