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

Colorectal Cancer Clinical Trial

Official title:

Effect of Folate on Colonic and Blood Cells

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00611000
• Other study ID #: CDR0000582113
• Secondary ID: RUH-PHO-0514-030
• Status: Completed
• Phase: Phase 1
• First received: February 7, 2008
• Last updated: February 14, 2009
• Start date: June 2003

Study information

• Verified date: February 2008
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. primary completion date: January 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 72 Years

Eligibility

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)

Study Design

Masking: Single Blind, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Colorectal Cancer

Intervention

Dietary Supplement:
• folic acid

Genetic:
• DNA methylation analysis

• gene expression analysis

• microarray analysis

• polymorphism analysis

Other:
• laboratory biomarker analysis

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Rockefeller University	National Cancer Institute (NCI)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DNA uracil incorporation in peripheral blood mononuclear cells (PBMCs)			No
Primary	Strand breaks in the coding region of p53 in PBMCs and rectal biopsy cells			No
Primary	DNA methylation (overall, p53 coding, p16 promoter, MLH1 promoter) in PBMCs and rectal biopsy cells			No
Secondary	Differential gene expression in colonic and PBMCs by microarray analysis			No