KINETICS OF FOLATE METABOLISM

叶酸处理的细胞中叶酸池动态的最新观察结果 甲氨蝶呤或甲氨蝶呤显示了不同的叶酸消耗 在乳腺癌和结肠癌细胞系中的应答比在肝癌细胞系中的应答更高。 对这种差异的解释是从以下方面寻求的： 叶酸循环的生化动力学。 叶酸循环生化 用网络模型预测酶活性 已知存在于几种结肠癌细胞系中的差异是 足以引起观察到的叶酸消耗的不同模式。 胸苷酸合成酶升高十倍和四十倍的细胞 (TS)预测活性显示几乎完全的叶酸消耗 当暴露于1 μ（M）剂量的甲氨蝶呤（MTX）时。 实验 已在NCI医学分支完成，选择了两个细胞系 对于这些增加的活性水平（加上对照）， 暴露于1 μ（M）和10 μ（M）剂量的MTX。 比较 人类结肠线数据的理论估计主要基于 在所有非零剂量和TS下，人乳腺线参数均显示一致性 活动 然而，在细胞系中缺乏与正常细胞的一致性。 暴露于较高MTX剂量的TS活性;理论预测短期 增加10-甲酰四氢叶酸，而实验表明， 快速下降。 可能，这种差异是由于代表性过高 TS对MTX多聚谷氨酸抑制的敏感性， 在较大的药物剂量下明显。

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.