Colorectal Adenomas, Calcium and Vitamin D Open Access

Fedirko, Veronika (2009)

Permanent URL: https://etd.library.emory.edu/concern/etds/r494vk98q?locale=en
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Abstract

Colorectal cancer is the second cause of cancer death in the US, and despite advances in treatment, screening, and prevention, its mortality has declined only modestly in recent years. Thus, there is need to develop new chemopreventive agents for colorectal neoplasms, and for new clinically accepted pre-neoplastic biomarkers of risk for colorectal neoplasms that may be used in colorectal cancer screening and in chemoprevention trials to assess the effectiveness of treatment. The goals for this dissertation are to investigate the roles of two evidentially well-supported chemopreventive agents, vitamin D3 and calcium, in colorectal carcinogenesis, and to develop modifiable biomarkers of risk for colorectal neoplasia.

In a pooled analysis of three colonoscopy based case-control studies, a substantial, statistically significant, lower risk for incident, sporadic colorectal adenomas was found with higher levels of circulating 25-(OH)-vitamin D3. This inverse association was stronger among those who took aspirin or other non-steroidal anti-inflammatory drugs. In a pilot randomized, double-blind, placebo-controlled clinical trial of calcium and vitamin D3 supplementation, modulation of expression of cell cycle biomarkers in the normal-appearing colorectal mucosa of patients with previously resected colorectal adenomas was found in the calcium and vitamin D3 groups. The strongest treatment effects were on the markers of cell differentiation and apoptosis, and vitamin D3 related. Findings from this clinical trial also support a new hypothesis that vitamin D3 and calcium reduce oxidative DNA damage in the colon, especially among those who have higher colorectal expression of the vitamin D receptor.

In conclusion, the results of my dissertation support hypotheses that higher intakes of vitamin D3 and calcium favorably modulate biomarkers of risk for colorectal neoplasms, and higher circulating 25-(OH)-vitamin D3 levels are associated with lower risk for incident, sporadic colorectal adenoma. The results of this dissertation warrant further investigation of the expression of cell cycle biomarkers in the normal-appearing colorectal mucosa as potential modifiable biomarkers of risk for colorectal neoplasms.

Table of Contents

TABLE OF CONTENTS

ILLUSTRATIONS
LIST OF TABLES
CHAPTER 1. INTRODUCTION AND BACKGROUND .................................................................. 1
Introduction ................................................................................................................ 1
Background ..................................................................................................................3
Overview of Colorectal Cancer Epidemiology .......................................................................3
Morphology of the Colon ................................................................................................ 6
Colon Carcinogenesis .................................................................................................... 7
Risk Factors for Colorectal Cancer ........................................................................... ......13
Calcium and Colorectal Adenomas .................................................................................. 29
Vitamin D and Colorectal Adenomas .................................................................................32
Calcium, Vitamin D and Colorectal Adenomas .....................................................................41
Modifiers of Calcium and Vitamin D Effects ........................................................................43
Effects of Calcium and/or Vitamin D on Cell Proliferation ..................................................... 44
Effects of Calcium and/or Vitamin D on Cell Apoptosis ........................................................ 47
Effects of Calcium and/or Vitamin D on Cell Differentiation .................................................. 49
Calcium, Vitamin D, and Oxidative Stress ......................................................................... 51
Hypotheses ................................................................................................................54
Objectives ..................................................................................................................55
Specific Aims .............................................................................................................. 55
Methods......................................................................................................................58
Data Analysis Plan ....................................................................................................... 60
Statistical Power Considerations ..................................................................................... 61
Student Contribution to Data Collection ........................................................................... 63
Study Strengths .......................................................................................................... 64


CHAPTER 2. BLOOD 25-HYDROXYVITAMIN D3 CONCENTRATIONS AND
INCIDENT, SPORADIC COLORECTAL ADENOMA RISK: A POOLED CASE-
CONTROL STUDY ......................................................................................................... 66
Abstract .................................................................................................................... 67
Introduction ............................................................................................................... 68
Materials and Methods ................................................................................................. 70
Results ..................................................................................................................... 79

Discussion ................................................................................................................. 82
Tables and Figures ...................................................................................................... 93


CHAPTER 3. EFFECTS OF VITAMIN D AND CALCIUM SUPPLEMENTATION
ON MARKERS OF APOPTOSIS IN NORMAL COLON MUCOSA: A
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL
............................................................................................................................... 106
Abstract ................................................................................................................... 107
Introduction .............................................................................................................. 108
Patients and Methods ..................................................................................................110
Results .................................................................................................................... 119
Discussion ................................................................................................................ 121
Tables and Figures ..................................................................................................... 127


CHAPTER 4. EFFECTS OF VITAMIN D AND CALCIUM SUPPLEMENTATION
ON MARKERS OF PROLIFERATION AND DIFFERENTIATION IN NORMAL
COLON MUCOSA: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED CLINICAL TRIAL ........................................................................................ 136
Abstract ................................................................................................................... 137
Introduction .............................................................................................................. 138
Patients and Methods ................................................................................................. 140
Results .................................................................................................................... 146
Discussion ................................................................................................................ 149
Tables and Figures ..................................................................................................... 157


CHAPTER 5. EFFECTS OF VITAMIN D AND CALCIUM SUPPLEMENTATION
ON MARKERS OF DNA DAMAGE IN NORMAL COLON MUCOSA: A
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL
............................................................................................................................... 165
Abstract ................................................................................................................... 166
Introduction .............................................................................................................. 167
Patients and Methods ................................................................................................. 168
Results .................................................................................................................... 176
Discussion ............................................................................................................... 179
Tables and Figures .................................................................................................... 187


CONCLUSIONS AND PUBLIC HEALTH IMPLICATIONS ......................................................... .196
FUTURE DIRECTIONS ................................................................................................ .199

REFERENCES..............................................................................................................204


APPENDIX. Laboratory Procedures ................................................................................. 240
Protocol for Biopsy Specimen Processing and Immunohistochemical Staining .......................... 240

Protocol for Quantifying Staining Density of Immunohistochemically Detected Biomarkers in Normal Colon Crypts ("Scoring").....242
Protocol for Measuring Plasma 25-(OH)- and 1,25-(OH)2 - Vitamin D Levels (CaDvMAP Study)....246
Protocol for Genotyping of the VDR BsmI Polymorphism (CaDvMAP Study) ....246
Protocol for 8-Hydroxy-2'-deoxyguanosine (8-OH-dG) Immunohistochemical (IHC) Staining ...248

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