FOLATE DEFICIENCY--PREVENTABLE RISK OF CANCER

我们建议调查的假设，可预防的状态叶酸 缺乏（FA-）使受影响的细胞更容易受到肿瘤的侵袭。 转型 以下意见支持了这一观点： 1)FA-在体内和体外产生严重的染色体损伤; 2）大的 组成性脆性染色体位点的数量，以FA-和 叶酸补充抑制，与断点相关 与人类恶性肿瘤相关，并在已知的 3）甲氨蝶呤是动物和人类中已知的共致癌原; 4)缺乏叶酸、蛋氨酸和胆碱的饮食会增强 许多致癌物质的致癌性; 5）先天性代谢缺陷 特征在于骨髓对叶酸的摄取缺陷， 非常高的白血病发病率; 6）叶酸补充剂可防止 发展，甚至逆转，宫颈发育不良的病变，在口腔 避孕药具使用者; 7）流行病学上， 注意到高癌症发病率和高频率的FA-在某些 人口。 从机械论上讲，我们假设在亏损状态下， 可利用的叶酸从核苷酸途径转移， 生物合成 由此导致的嘌呤核苷酸供应不足， 胸苷酸将：a）延长有丝分裂并在S期积累细胞， 它们最容易受到致癌物的攻击，B）可能会损害DNA 修复. 我们建议：1）测试FA对引发的影响， 促进小鼠皮肤肿瘤的发生; 2）测试FA-对小鼠皮肤肿瘤发生的影响。 和促进甲基亚硝基脲（MNU）引发的大鼠乳腺肿瘤; 3)证明假设的叶酸辅酶从 通过组织的直接HPLC分析FA中的核苷酸生物合成途径 叶酸;和4）比较的形成程度和持久性， 甲基化DNA加合物和大分子损伤（链断裂，碱 FA-和FA+大鼠暴露于单剂量的 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.