FOLATE DEFICIENCY--PREVENTABLE RISK OF CANCER

我们建议研究叶酸可预防状态的假设

We propose to investigate the hypothesis that preventable states of folate deficiency (FA-) render the affected cells more susceptible to neoplastic transformation. Support for this comes from the following observations: 1) FA- produces severe chromosomal damage in vivo and in vitro; 2) A large number of constitutive fragile chromosomal sites, expressed in FA- and suppressed by folate supplementation, correlate with break-points associated with human malignancy and map in the vicinity of known oncogenes; 3) Methotrexate is a known co-carinogen in animals and humans; 4) Diets devoid of folic acid, methionine and choline potentiate the carcinogenicity of many carcinogens; 5) An inborn error of metabolism characterized by defective bone marrow uptake of folates is associated with very high incidence of leukemias; 6) Folate supplementation prevents the progression, and even reverses, lesions of cervical dysplasia in oral contraceptive users; and 7) Epidemiologically, an association has been noted between high cancer incidence and high frequency of FA- in certain populations. Mechanistically we postulate that in the deficient state, available folates are shifted away from the pathways of nucleotide biosynthesis. The resulting inadequate supply of purine nucleotides and thymidylate will: a) prolong mitosis and accumulate cells at S phase when they are most vulnerable to carcinogen attack, and b) presumably impair DNA repair. We propose to 1) Test the effect of FA on the initiation and promotion of mouse skin tumors; 2) Test the effect of FA- on the initiation and promotion of methylnitrosourea (MNU)- initiated mammary tumors in rats; 3) Demonstrate the postulated shift in folate coenzymes away from the nucleotide biosynthesis pathways in FA by direct HPLC analysis of tissue folates; and 4) Compare the extent of formation and persitence of methylated DNA adducts and macromolecular damage (strand breakage, alkali labile sites) in the DNA of FA- and FA+ rats exposed to a single dose of radioactive MNU.