title: Ability of potent vitamin D3 analogs to inhibit growth of prostate cancer cells in vivo.
abstract: BACKGROUND
  Studies have identified analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], which in vitro are 10- to 3,000-fold more active than 1,25(OH)2D3. We compared in vivo the anti-cancer activity of three potent vitamin D3 analogs and 1,25(OH)2D3 at near to each of their maximal tolerated dose (MTD).
  
  
  METHODS
  Human LNCaP prostate cancer xenografts were grown in nude mice and the animals were treated with intraperitoneal injections of either diluant; 1,25(OH)2D3; 1,25-Dihydroxy-20epi-22-oxa-24,26,27-trisho-mocholecalciferol (KH 1060); 1,25-Dihydroxy-22E,24E-diene-24,26,27-trishomocholecalciferol (EB 1039); and 1,25-Dihydroxy-16-ene-24-oxo-19-norcholecalciferol (RO 26-9114). Tumor sizes were measured weekly and tumor weights were measured at autopsy on the 12th week.
  
  
  RESULTS
  Each of the analogs equally and markedly inhibited growth of the prostate cancer xenografts. The 1,25(OH)2D3 initially inhibited growth but, by the time of sacrifice, the tumors were nearly the same size as diluant controls. The histological examination of the tumors showed that the analogs produced tumor necrosis and microcalcification. None of the mice developed hypercalcemia, which is the major toxicity of vitamin D3 compounds.
  
  
  CONCLUSIONS
  The MTD of the analogs varied by 400-fold but each had similar efficacy suggesting that, when choosing a vitamin D analog for clinical study, overall efficacy without toxicity is more important than the total amount of the compound that can be administered. In summary, we have identified three vitamin D analogs that show marked potency in vivo to inhibit growth of human prostate cancer xenografts; each had no detectable toxicity. This study should help lay the foundation for clinical studies.
authors.affiliation: Cedars-Sinai Medical Center/UCLA School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Vegesna
authors.forename: James
authors.initials: J
authors.lastname: O'Kelly
authors.forename: Jonathan
authors.initials: J
authors.lastname: Said
authors.forename: Milan
authors.initials: M
authors.lastname: Uskokovic
authors.forename: Lise
authors.initials: L
authors.lastname: Binderup
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D002762:Cholecalciferol