Effects of vitamin d and calcium on proliferation and differentiation in normal colon mucosa: a randomized clinical trial.
To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop "treatable" phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months. Overall expression and distributions of p21(waf1/cip1) (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P = 0.03), 242% (P = 0.005), and 25% (P = 0.47), respectively, along the full lengths of colorectal crypts after 6 months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P = 0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may "normalize" the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms.
Fedirko
Veronika
V
Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
Bostick
Roberd M
RM
Flanders
W Dana
WD
Long
Qi
Q
Sidelnikov
Eduard
E
Shaukat
Aasma
A
Daniel
Carrie R
CR
Rutherford
Robin E
RE
Woodard
Jill Joelle
JJ
D000328:Adult; D000368:Aged; D002118:Calcium / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002762:Cholecalciferol / Q000494:pharmacology*; D003106:Colon / Q000166:cytology* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000517:prevention & control; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010919:Placebos; D011379:Prognosis; D019098:Telomerase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004338:Drug Combinations; D010919:Placebos; D002762:Cholecalciferol; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases; C509186:TERT protein, human; D019098:Telomerase; D002118:Calcium