Mamont P S, Siat M, Joder-Ohlenbusch A M, Bernhardt A, Casara P
Eur J Biochem. 1984 Aug 1;142(3):457-63. doi: 10.1111/j.1432-1033.1984.tb08308.x.
DL-alpha-Difluoromethylornithine (F2MeOrn), the most widely-used inhibitor of L-ornithine decarboxylase, has been a useful tool to demonstrate that polyamine biosynthesis is required to maintain maximum rates of cell proliferation. However, in most eukaryotic cell systems, F2MeOrn exerts cytostatic rather than cytotoxic effects. This may be due to the fact that this inhibitor creates only incomplete polyamine deficiency. In particular, F2MeOrn scarcely depletes intracellular spermine levels. We now demonstrate in rat hepatoma tissue culture (HTC) cells that (2R, 5R)-6-heptyne-2,5-diamine, a more potent irreversible inhibitor of L-ornithine decarboxylase than F2MeOrn, decreases the concentrations of all polyamines including spermine. In parallel with the depletion of these amines, there is a progressive decrease in the rate of cell proliferation and in cell viability. Restoration of the intracellular polyamine content, by addition to the medium of polyamines or a high concentration of L-ornithine, the substrate of L-ornithine decarboxylase, further demonstrates that the antiproliferative effects of (2R, 5R)-6-heptyne-2,5-diamine do result from polyamine deficiency. These findings support the concept that polyamines play an essential function in the cell division processes and emphasize the vital function of spermine in mammalian cells.
DL-α-二氟甲基鸟氨酸（F2MeOrn）是使用最广泛的L-鸟氨酸脱羧酶抑制剂，它是一种有用的工具，可用于证明维持细胞增殖的最大速率需要多胺生物合成。然而，在大多数真核细胞系统中，F2MeOrn发挥的是细胞生长抑制作用而非细胞毒性作用。这可能是由于这种抑制剂只会造成不完全的多胺缺乏。特别是，F2MeOrn几乎不会耗尽细胞内的精胺水平。我们现在在大鼠肝癌组织培养（HTC）细胞中证明，（2R，5R）-6-庚炔-2,5-二胺，一种比F2MeOrn更有效的L-鸟氨酸脱羧酶不可逆抑制剂，会降低包括精胺在内的所有多胺的浓度。与这些胺类物质的耗尽同时发生的是，细胞增殖速率和细胞活力逐渐下降。通过向培养基中添加多胺或高浓度的L-鸟氨酸（L-鸟氨酸脱羧酶的底物）来恢复细胞内多胺含量，进一步证明了（2R，5R）-6-庚炔-2,5-二胺的抗增殖作用确实是由多胺缺乏引起的。这些发现支持了多胺在细胞分裂过程中发挥重要作用的概念，并强调了精胺在哺乳动物细胞中的重要功能。
