title: Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts.
abstract: BACKGROUND
  Growing evidence supports the idea that de novo steroidogenesis has an important role in prostate cancer's progression to the castration-resistant state following androgen deprivation therapy. Therefore, reducing the availability of cholesterol for use as a precursor in androgen synthesis may reduce proliferation and disease progression.
  
  
  METHODS
  LNCaP xenograft-bearing mice were castrated and administered simvastatin via diet, and tumor volume and PSA concentration were monitored for 8 weeks post castration. Levels of serum and intratumoral androgens along with serum simvastatin and common toxicity markers were measured at end point.
  
  
  RESULTS
  Reduced post-castration tumor growth rate in simvastatin-treated mice correlated with delayed time to castration-resistant progression, determined by two serum PSA doublings from post-castration nadir, when compared with xenografts in mice on control diet. At 8 weeks post castration, serum simvastatin levels were comparable to clinically relevant human doses with no evidence of overt muscle or liver toxicity. This suppressed post-castration tumor growth in the simvastatin diet group was correlated with reduced intratumoral testosterone and dihydrotestosterone levels.
  
  
  CONCLUSIONS
  Reduced tumor growth and intratumoral androgen levels observed in simvastatin-treated, castrated mice harboring LNCaP xenograft suggests that suppressing de novo steroidogenesis can delay castration-resistant progression of this tumor model.
authors.affiliation: Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.|Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: J A
authors.initials: JA
authors.lastname: Gordon
authors.affiliation: Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.|Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Midha
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Szeitz
authors.affiliation: Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Ghaffari
authors.affiliation: Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: H H
authors.initials: HH
authors.lastname: Adomat
authors.affiliation: Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: T L
authors.initials: TL
authors.lastname: Klassen
authors.affiliation: Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: E S
authors.initials: ES
authors.lastname: Guns
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.|College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, BC, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Wasan
authors.affiliation: Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: M E
authors.initials: ME
authors.lastname: Cox
mesh_terms: D000284:Administration, Oral; D000728:Androgens / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019821:Simvastatin / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D002784:Cholesterol; D019821:Simvastatin; D017430:Prostate-Specific Antigen