title: Effects of the 5 alpha-reductase inhibitor dutasteride on gene expression in prostate cancer xenografts.
abstract: BACKGROUND
  In the prostate, androgens play a crucial role in normal and cancerous growth; hence the androgenic pathway has become a target of therapeutic intervention. Dutasteride is a 5 alpha-reductase (5AR) inhibitor currently being evaluated both for chemoprevention and treatment of prostate cancer. Dutasteride inhibits both 5AR I and II enzymes, effectively blocking conversion of testosterone to dihydrotestosterone (DHT) in the prostate. This greatly reduces the amount of the active ligand DHT available for binding to the androgen receptor (AR) and stimulating proliferation, making this a good candidate for chemoprevention of prostate cancer. In this study, we sought to determine how dutasteride is functioning at the molecular level, using a prostate cancer xenograft model.
  
  
  METHODS
  Androgen-responsive LuCaP 35 xenograft tumors were grown in Balb/c mice. Subcutaneously implanted time-release pellets were used for drug delivery. Microarray analysis was performed using the Affymetrix HG-U133Av2 platform to examine changes in gene expression in tumors following dutasteride treatment.
  
  
  RESULTS
  Dutasteride significantly reduced tumor growth in LuCaP 35 xenografts by affecting genes involved in apoptotic, cytoskeletal remodeling, and cell cycle pathways among others. Notably, genes in the Rho GTPase signaling pathway, shown to be important in androgen-deprivation conditions, were significantly up-regulated.
  
  
  CONCLUSIONS
  We have identified multiple pathways outside of the androgenic pathway in prostate cancer xenografts affected by treatment with dutasteride. These findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of agents that can be used in combination with this drug to further enhance its effectiveness.
authors.affiliation: Department of Urology Research, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Schmidt
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Regan
authors.forename: S Keith
authors.initials: SK
authors.lastname: Anderson
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.forename: Karla V
authors.initials: KV
authors.lastname: Ballman
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
mesh_terms: D000728:Androgens / Q000172:deficiency; D000818:Animals; D001378:Azasteroids / Q000008:administration & dosage*; D002455:Cell Division / Q000187:drug effects; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors*; D003692:Delayed-Action Preparations; D004343:Drug Implants; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000728:Androgens; D001378:Azasteroids; D003692:Delayed-Action Preparations; D004343:Drug Implants; D004791:Enzyme Inhibitors; D042944:Cholestenone 5 alpha-Reductase; D020741:rho GTP-Binding Proteins; D000068538:Dutasteride
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