title: Phase IIa, randomized placebo-controlled trial of single high dose cholecalciferol (vitamin D3) and daily Genistein (G-2535) versus double placebo in men with early stage prostate cancer undergoing prostatectomy.
abstract: OBJECTIVE
  Prostate cancer (PCa) represents an important target for chemoprevention given its prolonged natural history and high prevalence. Epidemiologic and laboratory data suggest that vitamin D and genistein (soy isoflavone) may decrease PCa progression. The effect of vitamin D on prostate epithelial cell proliferation and differentiation is well documented and genistein may augment this affect through inhibition of the CYP24 enzyme, which is responsible for intracellular vitamin D metabolism. In addition, both genistein and vitamin D inhibit the intraprostatic synthesis of prostaglandin E2, an important mediator of inflammation. The objectives of this prospective multicenter trial were to compare prostate tissue calcitriol levels and down-stream related biomarkers in men with localized prostate cancer randomized to receive cholecalciferol and genistein versus placebo cholecalciferol and placebo genistein during the pre-prostatectomy period.
  
  
  METHODS
  Men undergoing radical prostatectomy were randomly assigned to one of two treatment groups: (1) cholecalciferol (vitamin D3) 200,000 IU as one dose at study entry plus genistein (G-2535), 600 mg daily or (2) placebo cholecalciferol day 1 and placebo genistein PO daily for 21-28 days prior to radical prostatectomy. Serum and tissue analyses were performed and side-effects recorded.
  
  
  RESULTS
  A total of 15 patients were enrolled, 8 in the placebo arm and 7 in the vitamin D3+ genistein (VD + G) arm. All patients were compliant and completed the study. No significant differences in side effect profiles were noted. Utilization of the VD + G trended toward increased calcitriol serum concentrations when compared to placebo (0.104 ± 0.2 vs. 0.0013 ± 0.08; p=0.08); however, prostate tissue levels did not increase. Calcidiol levels did not change (p=0.5). Immunohistochemistry for marker analyses using VECTRA automated quantitation revealed a increase in AR expression (p=0.04) and a trend toward increased TUNEL staining (p=0.1) in prostate cancer tissues in men randomized to receive VD + G compared to placebo.
  
  
  CONCLUSIONS
  In this first study testing the combination of a single, large dose of cholecalciferol and daily genistein, the agents were well tolerated. While an increase in AR expression suggesting differentiation was observed, it is difficult to draw firm conclusions regarding the bioactivity of the combination given the sample size.
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public HealthMadison, WI, USA; Environmental and Molecular Toxicology, University of WisconsinMadison, WI, USA; University of Wisconsin Carbone Cancer CenterMadison, WI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jarrard
authors.affiliation: Department of Urology, University of Minnesota Minneapolis, MN, USA.
authors.forename: Badrinath
authors.initials: B
authors.lastname: Konety
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin Madison, WI, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public HealthMadison, WI, USA; University of Wisconsin Carbone Cancer CenterMadison, WI, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Downs
authors.affiliation: Department of Pathology and Laboratory Medicine, University of WisconsinMadison, WI, USA; University of Wisconsin Carbone Cancer CenterMadison, WI, USA; School of Pharmacy, University of WisconsinMadison, WI, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Kolesar
authors.affiliation: Department of Biostatistics and Medical Informatics, University of WisconsinMadison, WI, USA; University of Wisconsin Carbone Cancer CenterMadison, WI, USA.
authors.forename: Kyung Mann
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Department of Biostatistics and Medical Informatics, University of WisconsinMadison, WI, USA; University of Wisconsin Carbone Cancer CenterMadison, WI, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Havighurst
authors.affiliation: Department of Urology, University of Minnesota Minneapolis, MN, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Slaton
authors.affiliation: National Cancer Institute Bethesda, MD, USA.
authors.forename: Margaret G
authors.initials: MG
authors.lastname: House
authors.affiliation: National Cancer Institute Bethesda, MD, USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Parnes
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public HealthMadison, WI, USA; University of Wisconsin Carbone Cancer CenterMadison, WI, USA.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
keywords: Cholecalciferol; active surveillence; genestein; prostate cancer