FOLATE DEFICIENCY--PREVENTABLE RISK OF CANCER

叶酸缺乏——可预防癌症风险

• 批准号: 3181137
• 负责人: CARLOS L KRUMDIECK
• 金额: $ 14.82万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3181137
• 关键词: DNA methylation; DNA repair; benzanthracenes; breast neoplasms; cancer risk; chemical carcinogenesis; chromosome aberrations; cocarcinogen; croton oil; dietary trace element; folate deficiency; high performance liquid chromatography; molecular oncology; mutagens; neoplasm /cancer genetics; neoplasm /cancer nutrition therapy; nitrosourea; nutrition related neoplasm /cancer; nutrition related tag; purine nucleotides; skin neoplasms; thymidine monophosphate; tumor promoters; vitamin therapy

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.

我们建议调查以下假设：叶酸的可预防状态 缺乏（FA-）使受影响的细胞更容易患肿瘤 转变。 对此的支持来自以下观察： 1）FA-在体内和体外产生严重的染色体损伤； 2）大 组成型脆弱染色体位点的数量，以 FA- 和 被叶酸补充剂抑制，与断点相关 与人类恶性肿瘤相关以及已知附近的地图 癌基因； 3) 甲氨蝶呤是一种已知的动物和人类共致癌物； 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）先天性新陈代谢错误 其特征是骨髓对叶酸的摄取有缺陷，与 白血病发病率非常高； 6) 补充叶酸可以预防 口腔中宫颈发育不良病变的进展，甚至逆转 避孕药具使用者； 7) 从流行病学角度来看，一个协会 注意到某些特定人群的高癌症发病率和高 FA- 频率之间的关系 人口。 从机制上讲，我们假设在缺陷状态下， 可用叶酸从核苷酸途径转移 生物合成。 由此导致嘌呤核苷酸供应不足 胸苷酸会： 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质的攻击，并且 b) 可能会损害 DNA 维修。 我们建议 1) 测试 FA 对启动和启动的影响 促进小鼠皮肤肿瘤； 2) 测试FA-对引发的影响 以及促进甲基亚硝基脲（MNU）引发的大鼠乳腺肿瘤； 3) 证明叶酸辅酶的假设转移远离 通过组织直接 HPLC 分析 FA 中的核苷酸生物合成途径 叶酸； 4) 比较形成和持续的程度 甲基化 DNA 加合物和大分子损伤（链断裂、碱 暴露于单剂量的 FA- 和 FA+ 大鼠 DNA 中的不稳定位点） 放射性 MNU。