Abstract

There is strong biological plausibility and animal experimental evidence for protection against colorectal cancer by calcium and vitamin D, calcium significantly reduced adenoma recurrence in a large clinical trial in humans (yet the previously reported observational evidence, although generally supportive, is inconsistent), and the observational literature strongly supports protection from vitamin D. A close physiological relationship between calcium and vitamin D has long been known. Yet, other than a possible reduction of colorectal epithelial cell proliferation by calcium, the effects of calcium and vitamin D, individually or jointly, on the normal human colorectal epithelium remain unknown. There have been no clinical trials involving vitamin D individually or jointly with calcium related to colorectal cancer chemoprevention in humans. There are currently no generally accepted pre-neoplastic biomarkers of risk for colorectal cancer. Based on recent advances in understanding the molecular basis of colorectal cancer, we developed a panel of newer, plausible, reliable, immunohistochemically detected biomarkers that provides molecular phenotyping of the normal appearing colorectal epithelium: 1) inflammation (COX-2), 2) the expression of genes involved in the normal structure and function of the colorectal epithelium that have been found to be altered early in the 2 major colorectal carcinogenesis pathways (ARC, B-catenin, E-cadherin, MSH2, MLH1), 3) a more complete picture of the cell cycle events in colorectal epithelial crypt cells (short and long-term proliferation: MIB-1 and telomerase; differentiation: p21; apoptosis inhibition and promotion: bcl-2, bax, and bak), and 4) autocrine/paracrine growth factors (TGFa, TGFB1 that has not yet been tested in a chemoprevention trial. To address these needs, we are currently conducting a preliminary, randomized, double-blind, placebo-controlled, 2x2 factorial chemoprevention trial (n = 88) of calcium 2,000 mg/day and vitamin D3 800 lU/day, alone and in combination vs placebo over 6 months in patients with recent removal of sporadic adenomatous colorectal polyps, to investigate their effects on.several of the individual (COX-2, ARC, MSH2, MLH1, MIB-1, hTERT, p21, bcl-2, bax, and bak) and combined components of our colorectal cancer risk biomarker panel. We will also examine study results stratified by NSAID use and Bsm I vitamin D receptor genotypes. The preliminary estimates of treatment effect sizes and variabilities will be used to refine the biomarker panel and study design and to calculate the needed sample size for a potential full-scale study. Herein, we propose adding B-catenin, E-cadherin, TGFa, and TGFB1 to the biomarker panel for this trial. We assert that using biological measurements of risk, as they have for ischemic heart disease, will result in a decline in colorectal cancer incidence and mortality. The proposed project is borne of this vision, and has intertwined missions of exploring the efficacy of 2 plausible and evidentially well-supported dietary agents, calcium and vitamin D, on the modulation of a plausible panel of molecular phenotypic biomarkers of risk for colorectal neoplasia. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA115230-01
Application #
6943335
Study Section
Special Emphasis Panel (ZCA1-SRRB-Q (J1))
Program Officer
Hartmuller, Virginia W
Project Start
2005-06-21
Project End
2007-05-31
Budget Start
2005-06-21
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$76,500
Indirect Cost

  Institution

Name
Emory University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322