Chemoprevention of chemically-induced mammary and colon carcinogenesis by 1alpha-hydroxyvitamin D5

J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):129-36. doi: 10.1016/j.jsbmb.2005.06.008. Epub 2005 Jul 26.


Epidemiological data as well as experimental models yield evidence for a protective effect of vitamin D against the genesis of several types of cancers. Given its toxic properties at effective concentrations, numerous analogs of vitamin D have been developed. We synthesized an analog of vitamin D(5), 1alpha-hydroxy-24-ethylcholechalciferol (1alpha(OH)D(5)) and previously reported on its anti-proliferative activities against several cancer cell lines. To further examine its chemopreventive potential, experiments were conducted to investigate the in vivo effects of 1alpha(OH)D(5) using the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model. Results showed that 1alpha(OH)D(5) (25 and 50microg/kg diet) decreased the incidence and multiplicity of mammary tumors in female Sprague-Dawley rats. In a subsequent study, the stage specific inhibition was investigated using the 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis model. While supplementation with of 1alpha(OH)D(5) (40microg/kg diet) showed no significant effects during the initiation phase, tumor incidence during the promotional stage was significantly (p<0.05) decreased by 37.5%. In the colon, 1alpha(OH)D(5) (25microg/kg diet) was highly effective (p<0.001) in inhibiting the development of azoxymethane (AOM)-induced Aberrant crypt foci (ACF) in CF-1 mice. Studies on the stage specific inhibitory effects of 1alpha(OH)D(5) in the colon demonstrated that animals receiving 1alpha(OH)D(5) (25microg/kg diet) during the initiation, promotion, and entire period had a reduction in ACF number of 71, 80 and 82%, respectively. Immunohistochemistry studies comparing the colons of animals receiving control versus 1alpha(OH)D(5) supplemented diets showed that 1alpha(OH)D(5) partly mediates its effects by regulating members of the oncogenic beta-catenin pathway. 1Alpha(OH)D(5) inhibited expression of beta-catenin and peroxisome proliferator-activated receptor beta, a beta-catenin-TCF-4 responsive gene, whereas it induced expression of VDR. Cumulatively, these studies support the chemopreventive properties of 1alpha(OH)D(5) against the development of breast and colon cancers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chemoprevention
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / prevention & control*
  • Diet
  • Female
  • Hydroxycholecalciferols / pharmacology*
  • Hydroxycholecalciferols / therapeutic use
  • Mammary Glands, Animal / drug effects*
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / prevention & control*
  • Methylnitrosourea / pharmacology
  • Molecular Conformation
  • Organ Specificity
  • Rats
  • Rats, Sprague-Dawley
  • Wnt1 Protein / metabolism
  • beta Catenin / metabolism


  • 1-hydroxyvitamin D5
  • Hydroxycholecalciferols
  • Wnt1 Protein
  • beta Catenin
  • Methylnitrosourea