Alvarez-Rodríguez Y, Ruano A, Valladares Y
Cancer Chemother Pharmacol. 1980;4(1):53-60. doi: 10.1007/BF00255460.
The effect of methotrexate (amethopterin) upon the MMT cell line was studied by time-lapse microcinematography, the plasma levels obtained after systemic administration of maximum tolerated doses of the drug in man being simulated in vitro. Cells in the logarithmic growth phase (large growth fraction population) were widely affected, although enough drug-resistant cells remained to regenerate the cell colony. Cells in the preconfluent growth phase (small growth fraction population) were less effected, because many cells were arrested at the GO-hase, outside the cell cycle. A drug-resistant colony always developed, making the drug therapy useless. The experiments showed that rescue treatment with leucovorin (citrovorum factor of folinic acid) was not effective either, because, at least on our experimental conditions, recovery of the mitotic activity was more rapid and the number of degenerating cells smaller with rescur treatment than with the conventional treatment. The results also suggested a new mechanism of methotrexate action in addition to the classic one of folic acid inhibition, which might consist in the inhibition of the production of formyl-methionyl-tRNA, part of the initiation complex in protein biosynthesis.
通过延时显微摄影术研究了甲氨蝶呤（氨甲蝶呤）对MMT细胞系的作用，体外模拟了人体全身给予该药物最大耐受剂量后获得的血浆水平。对数生长期的细胞（生长分数大的群体）受到广泛影响，尽管仍有足够的耐药细胞来再生细胞集落。汇合前期生长的细胞（生长分数小的群体）受影响较小，因为许多细胞停滞在G0期，处于细胞周期之外。总是会形成耐药集落，使得药物治疗无效。实验表明，用亚叶酸钙（甲酰四氢叶酸的醛氢叶酸因子）进行挽救治疗也无效，因为，至少在我们的实验条件下，挽救治疗时的有丝分裂活性恢复更快，退化细胞的数量比传统治疗时少。结果还提示，除了经典的叶酸抑制作用外，甲氨蝶呤作用还有一种新机制，可能在于抑制甲酰甲硫氨酰 - tRNA的产生，甲酰甲硫氨酰 - tRNA是蛋白质生物合成起始复合物的一部分。
