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Effect of Folate on DNA in Colon Tissue and Blood Samples From Patients at Increased Risk of Developing Colorectal Neoplasia

This study has been completed.
National Cancer Institute (NCI)
Information provided by:
National Cancer Institute (NCI) Identifier:
First received: February 7, 2008
Last updated: February 14, 2009
Last verified: February 2008

RATIONALE: Studying samples of blood and tissue from patients at risk of cancer in the laboratory may help doctors learn more about the effect of folate on DNA and identify biomarkers related to cancer.

PURPOSE: This phase I trial is studying the effect of folate on DNA in colon tissue and peripheral blood samples from patients at increased risk of developing colorectal neoplasia.

Condition Intervention Phase
Colorectal Cancer Dietary Supplement: folic acid Genetic: DNA methylation analysis Genetic: gene expression analysis Genetic: microarray analysis Genetic: polymorphism analysis Other: laboratory biomarker analysis Phase 1

Study Type: Interventional
Study Design: Masking: Single
Primary Purpose: Prevention
Official Title: Effect of Folate on Colonic and Blood Cells

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • DNA uracil incorporation in peripheral blood mononuclear cells (PBMCs)
  • Strand breaks in the coding region of p53 in PBMCs and rectal biopsy cells
  • DNA methylation (overall, p53 coding, p16 promoter, MLH1 promoter) in PBMCs and rectal biopsy cells

Secondary Outcome Measures:
  • Differential gene expression in colonic and PBMCs by microarray analysis

Estimated Enrollment: 20
Study Start Date: June 2003
Primary Completion Date: January 2006 (Final data collection date for primary outcome measure)
Detailed Description:


  • To analyze the effects of changes in levels of dietary folate intake on damage to DNA and repair capacity, mRNA expression, and DNA uracil incorporation in peripheral blood mononuclear cell and rectal biopsy cell samples from patients at increased risk for developing colorectal neoplasia.

OUTLINE: Patients are enrolled into 1 of 2 intervention groups..

  • Group I (folate depletion [in-patient]): Patients consume a weight-maintaining, average folate diet with no high folate-containing foods for 8 weeks. Patients are then admitted to The Rockefeller University Hospital and placed on a weight-maintaining, low-folate diet for 12 weeks. During the last 4 weeks of the in-patient period, patients receive oral folic acid supplementation once daily for 4 weeks.
  • Group II (folate supplementation [out-patient]): Patients consume a weight-maintaining, average folate diet with no high folate-containing foods for 16 weeks as an out-patient. After the first 8 weeks of the diet, patients also receive oral folic acid supplementation once daily for 8 weeks.

Patients undergo blood sample collection periodically for biomarker correlative studies. Samples are analyzed for serum and red cell folate and homocystine levels to assess folate depletion; methylentetrahydrofolate reductase (MTHFR) polymorphism to test for inherited alterations of folate metabolism; serum and plasma biomarkers; and DNA studies. Patients also undergo tissue sample collection by sigmoidoscopy and rectal biopsy periodically. Tissue samples are assessed for mucosal folate concentration and mucosal folic acid metabolites; DNA methylation; and gene assays by microarray analysis.

After completion of study intervention, patients are followed at 4 weeks.


Ages Eligible for Study:   40 Years to 72 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • At increased risk for developing colorectal neoplasia due to 1 of the following:

    • Personal history of colorectal adenomatous polyps
    • Family history of colorectal adenoma or adenocarcinoma
  • No hereditary nonpolyposis colorectal cancer (HNPCC)
  • No more than one first-degree family member with colorectal or endometrial malignancies


  • Ambulatory
  • Female patients must be ≥ 2 years post-menopausal (i.e., 2 years after the last menstrual period)
  • Negative pregnancy test
  • Male patients must use effective contraception during and for 2 months after completion of study treatment (for male patients enrolled in the folate depletion group)
  • Serum folate level ≤ 20 ng/mL
  • Plasma vitamin B12 level ≥ 250 pg/mL
  • Serum homocysteine level ≤ 17 μmol/L
  • ALT or AST ≤ 2 times upper limit of normal
  • No unexplained elevated alkaline phosphatase
  • Creatinine ≤ 2.0 mg/dL
  • HIV negative
  • No folate metabolism abnormalities or predisposing conditions
  • No prior malignancy except nonmelanoma skin cancer
  • No intestinal malabsorption or inflammatory bowel disease
  • No excessive bleeding or coagulation disorder
  • No untreated hyperthyroidism
  • No diabetes mellitus requiring insulin
  • No daily alcohol intake > 2 ½ shot glasses of whisky or three 8-ounce glasses of beer or wine
  • No sustained blood pressure > 150/95 mm Hg for three consecutive readings
  • No other serious illness that would limit life expectancy to < 6 months


  • No prior gastrointestinal surgery, including gastrectomy or small or large bowel resections

    • Prior appendectomy or surgery of the esophagus allowed
  • More than 3 months since regular ingestion of ≥ 650 mg of aspirin (≥ 2 tablets of 325 mg regular strength OR > 1 tablet of 500 mg extra strength aspirin) per day

    • The following drugs are allowed for cardiovascular prophylaxis provided the patient has been taking the drug regularly for ≥ 1 month and continues to take the same dose during study participation:

      • One or two regular strength aspirin tablets (i.e., 325 mg per tablet) per day
      • One baby aspirin tablet (81 mg tablet) per day
  • More than 3 months since regular daily ingestion of other non-steroidal anti-inflammatory drugs (NSAIDs)
  • No concurrent anticoagulation therapy
  • No concurrent sterol-binding resins, such as cholestyramine (for the treatment of high blood cholesterol)
  • No other concurrent investigational drugs
  • No other concurrent medications that might, in the view of the study physicians, alter rectal mucosal proliferation, folate metabolism, or renal/hepatic metabolism
  • No concurrent weight control medications
  • No concurrent supplemental folate preparation containing > 400 mcg of folic acid per day
  • No concurrent hormone replacement therapy, including oral, transplanted, or injected contraceptives

    • Concurrent thyroid hormone replacement allowed provided the patient is euthyroid
  • No concurrent medication interfering with folic acid metabolic effects, including any of the following:

    • Methotrexate
    • Phenytoin
    • Phenobarbital
    • Primidone
    • Sulfonamides
    • Folinic acid derivatives
  • No concurrent lipid-lowering medications other than usual doses of the class of drugs known as statins

    • The following statin drugs are allowed provided the patient has been taking the drug regularly for ≥ 1 month and continues to take the same dose during study participation:

      • Atorvastatin (10 or 20 mg/day)
      • Fluvastatin (20 mg or 40 mg/day)
      • Lovastatin (10 or 20 mg/day)
      • Pravastatin (10 or 20 mg/day)
      • Simvastatin (5 or 10 mg/day)
  Contacts and Locations
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Please refer to this study by its identifier: NCT00611000

Sponsors and Collaborators
Rockefeller University
National Cancer Institute (NCI)
Principal Investigator: Peter R. Holt, MD Rockefeller University
  More Information Identifier: NCT00611000     History of Changes
Other Study ID Numbers: CDR0000582113
Study First Received: February 7, 2008
Last Updated: February 14, 2009

Keywords provided by National Cancer Institute (NCI):
colon cancer
rectal cancer

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Folic Acid
Vitamin B Complex
Growth Substances
Physiological Effects of Drugs processed this record on September 20, 2017