Pegg A E, Secrist J A, Madhubala R
Department of Physiology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
Cancer Res. 1988 May 15;48(10):2678-82.
L1210 cells were selected for resistance to the ornithine decarboxylase (ODC) inhibitor, alpha-difluoromethylornithine. When grown in the absence of the inhibitor, these cells possessed very high ornithine decarboxylase levels. These represented about 1 part in 300 of the soluble protein, which is several hundred times greater than the maximal value found in the original L1210 cells. The resistant cells contained at least 100-fold higher levels of ODC mRNA but the half-life of ODC (about 45 min) was not altered significantly. The resistant cells had much higher putrescine and cadaverine levels than control cells, but there was no significant difference in cellular spermidine or spermine content or in production of 5'-methylthioadenosine, which is a measure of polyamine synthesis. Addition of putrescine to the control or resistant cells had no effect on their content of spermidine and spermine but addition of decarboxylated S-adenosylmethionine increased the content of spermidine and spermine. These results indicate that ornithine decarboxylase is not the rate-limiting step in polyamine synthesis in these L1210 cells. The growth of the alpha-difluoromethylornithine-resistant L1210 cells was inhibited when their ability to synthesize spermidine and spermine was blocked by the addition of the S-adenosylmethionine decarboxylase inhibitor, 5'-deoxy-5'-[N-methyl-N-(3-hydrazinopropyl)]aminoadenosine. Treatment with this compound produced a reduction of more than 85% in the production of 5'-methylthioadenosine and led to a large increase in the content of putrescine and a substantial decline in the content of spermidine and spermine. These results indicate the potential value of S-adenosylmethionine decarboxylase inhibitors as therapeutic agents in conditions where ODC inhibitors are ineffective.
选择L1210细胞使其对鸟氨酸脱羧酶（ODC）抑制剂α-二氟甲基鸟氨酸产生抗性。当在无抑制剂的情况下生长时，这些细胞具有非常高的鸟氨酸脱羧酶水平。这些水平约占可溶性蛋白质的1/300，比原始L1210细胞中发现的最大值高出数百倍。抗性细胞中ODC mRNA水平至少高100倍，但ODC的半衰期（约45分钟）没有明显改变。抗性细胞中的腐胺和尸胺水平比对照细胞高得多，但细胞内亚精胺或精胺含量或5'-甲基硫代腺苷（多胺合成的一种指标）的产生没有显著差异。向对照细胞或抗性细胞中添加腐胺对其亚精胺和精胺含量没有影响，但添加脱羧S-腺苷甲硫氨酸会增加亚精胺和精胺的含量。这些结果表明，鸟氨酸脱羧酶不是这些L1210细胞中多胺合成的限速步骤。当通过添加S-腺苷甲硫氨酸脱羧酶抑制剂5'-脱氧-5'-[N-甲基-N-（3-肼基丙基）]氨基腺苷来阻断其合成亚精胺和精胺的能力时，α-二氟甲基鸟氨酸抗性L1210细胞的生长受到抑制。用该化合物处理导致5'-甲基硫代腺苷的产生减少超过85%，并导致腐胺含量大幅增加，亚精胺和精胺含量大幅下降。这些结果表明，在ODC抑制剂无效的情况下，S-腺苷甲硫氨酸脱羧酶抑制剂作为治疗药物具有潜在价值。
