Chemoprevention of Colorectal Cancer: the Role of Non-digestible Carbohydrates

Study Overview
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Brief Summary
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Colorectal cancer is a common disease worldwide. It is now thought that colorectal cancer cells arise from stem cells where the genetic material regulating growth and division of the stem cell has become defective. This leads to unregulated production of cells which in turn have defective genetic information and cancer formation. Research into colorectal cancer is hampered by the fact that studies must take a very long time to produce results and be very large if the development of a cancer is the endpoint. Therefore alternative methods of quantifying the risk of developing a cancer are required so trials can be a realistic size and be completed in a realistic time frame. The investigators have previously identified several candidates for these 'biomarkers'. The next stage in proving or disproving these as useful biomarkers is to test their response to a dietary agent that the investigators know reduces the risk of colon cancer.

Detailed Description
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This project is designed to enhance understanding of links between food and the health of the gut. The particular purpose of the project is to investigate the impact of a well-defined intervention in human volunteers on a panel of novel, and established, diet-related biomarkers of bowel cancer risk. We have developed a number of novel biomarkers of diet-related CRC risk measured in colo-rectal mucosal biopsies (and in stool). These biomarkers include differentially expressed proteins, DNA methylation markers and inflammation markers. In our on-going BORICC Study we are investigating the relationships between dietary exposure and nutritional status for these biomarkers in a cross-sectional study. The next logical step in this research is to determine whether a selected panel of the most promising biomarkers responds to a dietary intervention i.e. to test their utility as biomarkers of GI health and potential as surrogate endpoints in future human studies. We propose to use Hi-maize 260 and polydextrose (PD) as our model resistant starch (RS) intervention agents. RS describes the fraction of dietary starch which is not digested in the small bowel and which flows to the colon where it is a substrate for bacterial fermentation. (Asp, 1996) PD is produced by the bulk melt polycondensation of glucose and sorbitol to produce an oligosaccharide with a mean degree of polymerisation of 12 which is resistant to mammalian GI enzymes and, like other RSs, is a substrate for bacterial fermentation. (Auerbach, 2007) Both Hi-maize and PD are fermented (to a greater or lesser extent) producing short-chain fatty acids (SCFA) including butyrate. (Asp, 1996) Butyrate has beneficial effects on gut physiology and immune function including anti-inflammatory effects. (Wächtershäuser, 2000; Dronamraju, 2009) In the present project we will investigate the impact of PD and RS, as food-borne substrates for delivery of butyrate, on biomarkers of bowel cancer risk.

Official Title
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Chemoprevention of Colorectal Cancer: the Role of Non-digestible Carbohydrates

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Dietary Supplement: Maltodextrin and Amioca starch
* Dietary Supplement: Hi-maize 260
* Dietary Supplement: Polydextrose
* Dietary Supplement: Hi-maize 260 and polydextrose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Attended for flexible sigmoidoscopy or colonoscopy and no macroscopic pathology identified Exclusion Criteria: Age <16 or >85 Familial polyposis syndrome Lynch syndrome Known colorectal tumour Previous colorectal resection Pregnancy Chemotherapy in last 6 months Therapy with aspirin/other NSAID Other immunosuppressive medication Active colonic inflammation at endoscopy Incomplete left sided examination Colorectal carcinoma found at endoscopy Iatrogenic perforation at endoscopy Colorectal cancer on histology Warfarin or other anticoagulant use Diabetes mellitus Crohn's disease Cognitive impairment

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Dietary Supplement: Maltodextrin and Amioca starch<br>* 12g Maltodextrin and 23g Amioca starch daily in divided doses for 50 days. Provided as a powder to be added to food or drink.<br>|
| Experimental: Hi-maize 260<br> | Dietary Supplement: Hi-maize 260<br>* 23g Hi-maize 260 and 12g Maltodextrin daily in divided doses for 50 days. Provided as a powder to be added to food or drink.<br>|
| Experimental: Polydextrose<br> | Dietary Supplement: Polydextrose<br>* 12g polydextrose and 23g amioca starch daily in divided doses for 50 days. Provided as a powder to be added to food or drink.<br>|
| Active Comparator: Hi-maize 260 and polydextrose<br> | Dietary Supplement: Hi-maize 260 and polydextrose<br>* 12g polydextrose and 23g Hi-maize 260 daily in divided doses for 50 days. Provided as a powder to be added to food or drink.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Faecal calprotectin concentration |  | 50 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum C reactive protein concentration |  | 50 days | 
| COX 2 expression in mucosal biopsies |  | 50 days | 
| Number and distribution of mitotic and apoptotic cells within colonic crypts (mucosal cell kinetics) |  | 50 days | 
| Cellular CDK 4 RNA expression |  | 50 days | 
| Cellular GADD45A RNA expression |  | 50 days | 
| Target gene methylation (p16, GSTP1, RARβ2, CDH1 GATA4 APC, SFRP1, 2, 4 and 5, AXIN2, DKK1 and WIF1) |  | 50 days | 
| Global genetic methylation |  | 50 days | 
| Cellular protein biomarker (CK8) expression |  | 50 days | 
| Faecal pH |  | 50 days | 
| Faecal bacterial abundance and population |  | 50 days | 
| Faecal short chain fatty acid concentration |  | 50 days | 
| Urinary short chain fatty acid concentration |  | 50 days | 
| Plasma short chain fatty acid concentration |  | 50 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biomarkers, Colorectal cancer, Resistant starch, Polydextrose, Non-digestible carbohydrate