title: Inhibition of 5alpha-reductase enhances testosterone-induced expression of U19/Eaf2 tumor suppressor during the regrowth of LNCaP xenograft tumor in nude mice.
abstract: BACKGROUND
  Intermittent androgen deprivation therapy (IADT) was developed to improve the quality of life and retard prostate cancer progression to castration resistance. IADT involves regrowth of the tumor during the off cycle upon testosterone recovery. Our previous studies showed that testosterone is more potent than dihydrotestosterone (DHT) in the induction of a subset of androgen-responsive genes during rat prostate regrowth. However, it is not clear if the same phenomenon would occur during androgen-induced regrowth of prostate tumors. Understanding the differences between testosterone and DHT in inducing androgen-responsive genes during prostate tumor regrowth may provide new insight for improving IADT.
  
  
  METHODS
  Nude mice bearing androgen-sensitive LNCaP xenograft were castrated and followed up for 7-10 days before being randomized into various androgen manipulations, consisting of continuous castration (C) or testosterone replacement (T) in the absence or presence of dutasteride (D), a 5alpha-reductase inhibitor that blocks the conversion of testosterone to DHT. Testes-intact animals in the absence or presence of D were used as controls. The expression of five androgen-responsive genes, including the tumor suppressor U19/Eaf2, was determined using real-time RT-PCR, 3 days after randomization.
  
  
  RESULTS
  In LNCaP tumors, the expression of U19/Eaf2 was higher in the T+D group as compared with T alone (2.87-fold, P < 0.05). In contrast, dutasteride treatment in testes-intact animals inhibited the expression of U19/Eaf2.
  
  
  CONCLUSIONS
  Inhibition of 5alpha-reductase during LNCaP tumor regrowth enhanced the expression of U19/Eaf2, an androgen-regulated tumor suppressor. This finding suggests that off cycle 5alpha-reductase inhibition may enhance the efficacy of IADT.
authors.affiliation: Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Shubham
authors.initials: S
authors.lastname: Gupta
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Raquel
authors.initials: R
authors.lastname: Ramos-Garcia
authors.forename: Daniel
authors.initials: D
authors.lastname: Shevrin
authors.forename: Joel B
authors.initials: JB
authors.lastname: Nelson
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000728:Androgens / Q000172:deficiency; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors*; D013196:Dihydrotestosterone / Q000378:metabolism; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics*; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics*; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000728:Androgens; D001378:Azasteroids; D004791:Enzyme Inhibitors; C483108:FESTA protein, mouse; D009687:Nuclear Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride; D042944:Cholestenone 5 alpha-Reductase; D017430:Prostate-Specific Antigen; D000068538:Dutasteride