Clinical Trial: Fish Oil Supplementation, Nutrigenomics and Colorectal Cancer Prevention

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Prevention

Brief Summary:

Colorectal cancer is the second leading cause of cancer-related death within the United States. Animal models and observational studies have suggested that marine-derived n-3 polyunsaturated fatty acids [PUFA] such as eicosapentanoic acid [EPA] and docosahexanoic acid [DHA] may reduce the risk of colorectal cancer. In addition, it may be the relative proportion of n-3 to n-6 PUFAs that best determines the chemopreventive effects of fish oils. This ratio is important because the n-6 PUFA, arachidonic acid (ARA), is converted via the cyclo-oxygenase (COX) pathway to prostaglandin E2 (PGE2), an inflammatory eicosanoid overproduced in colorectal neoplasms while EPA is converted to the anti-inflammatory prostaglandin E3 (PGE3). While the ratio of n-6 to n-3 PUFAs can be altered through dietary changes, genetic factors may also influence this ratio. Recent genetic studies have demonstrated that much of the tissue levels of ARA is determined by differences in a gene called fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion of linoleic acid, the most commonly consumed PUFA in the Western diet, to ARA, and one particular genetic variant caller rs174537 is associated with lower fatty acid desaturase activity and subsequently lower tissue levels of ARA.

The study hypothesis is that individuals with genetically determined lower activity of FADS1 will derive greater benefit from fish oil supplementation than individuals with higher FADS1 activity because of lower tissue levels of ARA and subsequently a more favorable n-6 to n-3 PUFA ratio. To test this hypothesis the investigators will recruit 150 participants with recently identified adenomatous polyps and conduct a 6-month double blind 3 X 2 factorial randomized controlled trial. The first factor will be FADS1 genotype (GG, GT, and TT) and the second factor will be fish oil supplementation (fish oil

Detailed Summary:

1.Rationale and Specific Aims

Colorectal cancer (CRC) is the third most common cancer and the second most frequent cause of cancer related mortality in the United States. Animal and human studies have suggested that the marine-derived n-3 polyunsaturated fatty acids (PUFAs), eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), have cancer inhibitory properties while conversely, n-6 PUFAs such as arachidonic acid (ARA) may promote tumorigenesis. The mechanism behind these opposing effects is likely due to differences in the biological activity of their eicosanoids end products and their effects on chronic inflammation. Prostaglandin E2 (PGE2) is a pro-inflammatory eicosanoid that is aberrantly produced in both colorectal adenomas and cancer and is derived from ARA via the cyclo-oxygenase pathway. EPA is converted through the same pathway into prostaglandin E3, which has 4 to 7- fold less prostaglandin E receptor affinity, is less inflammatory, and may even be pro-apoptotic compared to PGE2. As such, it may be the ratio of ARA to EPA and DHA rather than the absolute levels of marine-derived n-3 PUFAs that contribute most towards their antiproliferative and pro-apoptotic effects.

The ratio of ARA to EPA + DHA can be manipulated through fish oil supplementation, however; genetic factors may play a key role on determining this ratio. Recent genome-wide association and haplotype studies have demonstrated that up to 28% of the additive variance in tissue levels of ARA is explained by variants in a single gene, fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion of linoleic acid (LA), the most commonly consumed PUFA, to ARA, and homozygotes for the T allele (population frequency of 13%, HapMap -CEU) in rs174537 have lower fatty acid desaturase activity and subsequently lower tissue levels of A
Sponsor: Vanderbilt University

Current Primary Outcome:

  • rectal epithelial cell proliferation [ Time Frame: 6 month ]
    The primary outcome of interest is rectal epithelial cell proliferation, as measured by Ki67 (mib-1) labeling. Expression of Ki-67 in colon epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).
  • rectal epithelial cell apoptosis [ Time Frame: 6 moths ]
    The primary outcome of interest is rectal epithelial cell apoptosis as measured by TUNEL (TdT-mediated dUTP Nick-End Labeling). The TUNEL assay is conducted to measure apoptosis of colon epithelium using DeadEnd Colorimetric TUNEL System (Promega). After all fields of each sample are measured, the final immunoreaction indices are generated automatically by setting algorithms as ''total positive area / total nuclear area. Apoptotic activity is also scored using standard morphologic criteria applied to H&E stained sections.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Rectal epithelial cell COX-2 expression [ Time Frame: 6 months ]
    Expression of COX-2 in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).
  • Rectal epithelial cell 15-PGDH expression [ Time Frame: 6 months ]
    Expression of 15-PGDH in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).
  • Rectal epithelial cell phospholipid fatty acid content [ Time Frame: 6 months ]
    Lipids will be extracted using the method of Folch-Lees
  • Rectal epithelial cell production of PGE2 and PGE3 [ Time Frame: 6 months ]
    liquid chromatography/tandem mass spectrometric


Original Secondary Outcome: Same as current

Information By: Vanderbilt University Medical Center

Dates:
Date Received: August 7, 2012
Date Started: February 4, 2013
Date Completion: December 31, 2017
Last Updated: February 21, 2017
Last Verified: February 2017