FOLATE DEFICIENCY--PREVENTABLE RISK OF CANCER

我们建议调查叶酸可预防状态的假设 缺乏(FA-)使受影响的细胞更容易患上肿瘤 转型。对这一点的支持来自以下观察： 1)FA-在体内和体外都会造成严重的染色体损伤；2)大的 组成脆性染色体位置的数量，以FA-和表示 被叶酸补充抑制，与突破点相关 与人类的恶性肿瘤有关，并在已知的地图附近 3)甲氨蝶呤是一种已知的动物和人类的辅癌基因； 4)不含叶酸、蛋氨酸和胆碱的饮食会增强 多种致癌物的致癌性；5)先天的新陈代谢错误 以骨髓叶酸摄取缺陷为特征的与 白血病的发病率非常高；6)补充叶酸可预防 口腔宫颈异常增生症的进展，甚至逆转 避孕药使用者；以及7)流行病学方面，有一种关联 注意到高癌症发病率和高频率的FA-在某些 人口。从力学上讲，我们假设在亏缺状态下， 可利用的叶酸从核苷酸途径移开。 生物合成。由此导致的嘌呤核苷酸供应不足和 胸苷将：a)延长有丝分裂，并在S期积累细胞，当 它们最容易受到致癌物的攻击，b)可能会损害DNA 修理。我们建议1)测试FA对启动和启动的影响 对小鼠皮肤肿瘤的促进作用；2)检测FA-对小鼠皮肤肿瘤的诱导作用 促进甲基亚硝脲(MNU)诱发的大鼠乳腺肿瘤； 3)证明假设的叶酸辅酶从 组织直接高效液相分析FA的核苷酸生物合成途径 以及4)比较叶酸的形成和存在程度 甲基化DNA加合物和大分子损伤(链断裂、碱 在FA-和FA+大鼠的DNA中) 放射性MNU。

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.