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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
OBJECTIVES: 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.

Official Title
-----------------
Effect of Folate on Colonic and Blood Cells

Conditions
-----------------
Colorectal Cancer

Intervention / Treatment
-----------------
* Dietary Supplement: folic acid
* Genetic: DNA methylation analysis
* Genetic: gene expression analysis
* Genetic: microarray analysis
* Genetic: polymorphism analysis
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: 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 PATIENT CHARACTERISTICS: 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 PRIOR CONCURRENT THERAPY: 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)

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 72 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Masking: Single


Arms and Interventions

| Intervention/Treatment |
| --- |
|Dietary Supplement: folic acid|nan|
|Genetic: DNA methylation analysis|nan|
|Genetic: gene expression analysis|nan|
|Genetic: microarray analysis|nan|
|Genetic: polymorphism analysis|nan|
|Other: laboratory biomarker analysis|nan|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differential gene expression in colonic and PBMCs by microarray analysis |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
colon cancer, rectal cancer