KINETICS OF FOLATE METABOLISM

叶酸代谢动力学

• 批准号: 3852950
• 负责人: P F MORRISON
• 金额: --
• 依托单位: NATIONAL CENTER FOR RESEARCH RESOURCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3852950
• 关键词: breast neoplasms; cell line; chemical kinetics; colon neoplasms; enzyme activity; enzyme model; folate; human tissue; liver neoplasms; methotrexate; neoplasm /cancer chemotherapy; neoplastic cell; nutrition aspect of cancer; nutrition related tag; thymidylate synthase; tissue /cell culture; trimetrexate; vitamin metabolism

Recent observations of folate pool dynamics in cells treated with trimetrexate or methotrexate have revealed different folate depletion responses in breast and colon cancer cell lines than in hepatoma lines. An explanation of this difference is being sought in terms of the biochemical kinetics of the folate cycle. A folate cycle biochemical network model has been employed to predict that the enzyme activity differences known to exist across several colon cancer lines are sufficient to cause the diverse patterns of folate depletion observed. Cells with both ten- and fortyfold elevations in thymidylate synthase (TS) activity were predicted to exhibit nearly complete folate depletion when exposed to 1-mu(M) doses of methotrexate (MTX). Experiments have been completed in the Medicine Branch, NCI, on two cell lines selected for these increased levels of activity (plus controls) in which the cells were exposed to both 1-mu(M) and 10-mu(M) doses of MTX. Comparisons of the human colon line data with theoretical estimates based largely on human breast line parameters showed agreement at all nonzero doses and TS activities. Agreement, however, was lacking in the cell line with normal TS activity exposed to the higher MTX dose; theory predicted a short-term increase in 10-formyl tetrahydrofolate, while experimentation showed a rapid decrease. Possibly, this disparity is due to an overrepresentation of the sensitivity of TS to MTX polyglutamate inhibition, an effect more noticeable at larger drug doses.

最近对经处理的细胞中叶酸库动态的观察 三甲蝶呤或甲氨蝶呤显示出不同的叶酸消耗 乳腺癌和结肠癌细胞系中的反应高于肝癌细胞系。 正在寻求对这种差异的解释 叶酸循环的生化动力学。 叶酸循环生化 采用网络模型来预测酶活性 已知几种结肠癌系之间存在的差异是 足以导致观察到的不同叶酸消耗模式。 胸苷酸合酶升高十倍和四十倍的细胞 (TS) 活性预计会表现出几乎完全的叶酸耗尽 当暴露于 1-mu(M) 剂量的甲氨蝶呤 (MTX) 时。 实验有 已在 NCI 医学部门针对选定的两种细胞系完成 对于这些增加的活动水平（加上对照），其中细胞 暴露于 1-mu(M) 和 10-mu(M) 剂量的 MTX。 比较 人类结肠线数据的理论估计主要基于 人类乳腺线参数在所有非零剂量和 TS 下均表现出一致性 活动。 然而，细胞系与正常细胞缺乏一致性。 TS 活性暴露于较高的 MTX 剂量；理论预测短期 10-甲酰四氢叶酸增加，而实验表明 迅速减少。 这种差异可能是由于代表性过高造成的 TS 对 MTX 聚谷氨酸抑制的敏感性，效果更 在较大的药物剂量下更明显。