title: Phase II open label, multi-center clinical trial of modulation of intermediate endpoint biomarkers by 1α-hydroxyvitamin D2 in patients with clinically localized prostate cancer and high grade pin.
abstract: BACKGROUND
  Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention. Major risk factors for this disease have been associated with low serum levels of vitamin D. Here, we evaluate the biologic activity of a less calcemic vitamin D analog 1α-hydroxyvitamin D2 [1α-OH-D2] (Bone Care International, Inc.) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia (HG PIN).
  
  
  METHODS
  Patients with clinically organ-confined prostate cancer and HG PIN were randomized to 1α-OH-D2 versus placebo for 28 days prior to radical prostatectomy. Intermediate endpoint biomarkers included serum vitamin D metabolites, TGFß 1/2, free/total PSA, IGF-1, IGFBP-3, bFGF, and VEGF. Tissue endpoints included histology, MIB-1 and TUNEL staining, microvessel density and factor VIII staining, androgen receptor and PSA, vitamin D receptor expression and nuclear morphometry.
  
  
  RESULTS
  The 1α-OH-D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days. While serum vitamin D metabolite levels only slightly increased, evidence of biologic activity was observed with significant reductions in serum PTH levels. TGF-ß2 was the only biomarker significantly altered by vitamin D supplementation. Whether reduced TGF-ß2 levels in our study is an early indicator of response to vitamin D remains unclear.
  
  
  CONCLUSIONS
  While further investigation of vitamin D may be warranted based on preclinical studies, results of the present trial do not appear to justify evaluation of 1α-OH-D2 in larger clinical prostate cancer prevention studies.
authors: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. jason.r.gee@lahey.org
authors: Jason
authors: J
authors: Gee
authors: Howard
authors: H
authors: Bailey
authors: Kyungmann
authors: K
authors: Kim
authors: Jill
authors: J
authors: Kolesar
authors: Tom
authors: T
authors: Havighurst
authors: Kendra D
authors: KD
authors: Tutsch
authors: William
authors: W
authors: See
authors: Michael B
authors: MB
authors: Cohen
authors: Nick
authors: N
authors: Street
authors: Leon
authors: L
authors: Levan
authors: David
authors: D
authors: Jarrard
authors: George
authors: G
authors: Wilding
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D023381:Endpoint Determination; D004872:Ergocalciferols / Q000008:administration & dosage*; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007610:Kallikreins / Q000097:blood; D008297:Male; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D010919:Placebos; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood* / Q000098:blood supply / Q000188:drug therapy* / Q000601:surgery; D053773:Transforming Growth Factor beta1 / Q000097:blood; D053781:Transforming Growth Factor beta2 / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014807:Vitamin D / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D004872:Ergocalciferols; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D010919:Placebos; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D014807:Vitamin D; C042533:1 alpha-hydroxyergocalciferol; D007334:Insulin-Like Growth Factor I; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen