Porter C W, McManis J, Casero R A, Bergeron R J
Cancer Res. 1987 Jun 1;47(11):2821-5.
It has been shown previously (Porter et al., Cancer Res., 45: 2050-2057, 1985) that the N1,N8-bis(ethyl) derivative of spermidine has significant antiproliferative activity which appears to derive from its regulatory effects on the polyamine biosynthetic pathway, particularly on ornithine decarboxylase activity. In the present study, N1,N4-bis(ethyl)putrescine (BEP) and N1,N12-bis(ethyl)spermine (BESm) were compared with N1,N8-bis(ethyl)spermidine (BES) in their ability to inhibit cell growth and regulate polyamine biosynthesis. With cultured L1210 murine leukemia cells, the IC50 values at 48 h were approximately 2 mM for BEP, 30 microM for BES, and 1 microM for BESm making the latter the most effective polyamine inhibitor or analogue thus far identified. At concentrations which approximated IC50 values and yielded similar intracellular concentrations at 48 h (1500-2000 pmol/10(6) cells), the effects of the analogues on polyamine biosynthesis generally correlated with their antiproliferative activity. BEP, at 1 mM, exerted relatively minor effects on polyamine biosynthesis. By contrast, 100 microM BES totally eliminated ornithine decarboxylase activity, depleted putrescine and spermidine pools, and decreased spermine pools by 40%. AdoMet decarboxylase activity was lowered slightly. The most impressive effects were obtained with 10 microM BESm which decreased ornithine and AdoMet decarboxylase activities by 99 and 84%, respectively; depleted putrescine and spermidine pools; and decreased spermine pools by 73%. None of the analogues, at 1 or 3 mM, had significant direct inhibitory effects on the decarboxylase activities from untreated cells with the exception of BESm which inhibited ornithine but not AdoMet decarboxylase activity. Thus, the effects of the analogues on these enzymes in treated cells are presumed to be mainly mediated by regulatory mechanisms. In this regard, BESm was superior to BES since both ornithine and AdoMet decarboxylase activities were suppressed. Given its unique activities, BESm would seem to have potential as both an antiproliferative agent and also as an experimental probe for studying regulation of the polyamine pathway, particularly AdoMet decarboxylase.
先前的研究（Porter等人，《癌症研究》，45: 2050 - 2057, 1985）表明，亚精胺的N1,N8 - 双（乙基）衍生物具有显著的抗增殖活性，这似乎源于其对多胺生物合成途径的调节作用，特别是对鸟氨酸脱羧酶活性的调节。在本研究中，将N1,N4 - 双（乙基）腐胺（BEP）和N1,N12 - 双（乙基）精胺（BESm）与N1,N8 - 双（乙基）亚精胺（BES）在抑制细胞生长和调节多胺生物合成的能力方面进行了比较。对于培养的L1210小鼠白血病细胞，48小时时BEP的IC50值约为2 mM，BES为30 microM，BESm为1 microM，这使得BESm成为迄今为止鉴定出的最有效的多胺抑制剂或类似物。在接近IC50值且48小时时产生相似细胞内浓度（1500 - 2000 pmol/10(6)细胞）的浓度下，类似物对多胺生物合成的影响通常与其抗增殖活性相关。1 mM的BEP对多胺生物合成的影响相对较小。相比之下，100 microM的BES完全消除了鸟氨酸脱羧酶活性，耗尽了腐胺和亚精胺池，并使精胺池减少了40%。腺苷甲硫氨酸脱羧酶活性略有降低。使用10 microM的BESm获得了最显著的效果，它分别使鸟氨酸和腺苷甲硫氨酸脱羧酶活性降低了99%和84%；耗尽了腐胺和亚精胺池；并使精胺池减少了73%。除了BESm抑制鸟氨酸脱羧酶活性但不抑制腺苷甲硫氨酸脱羧酶活性外，1 mM或3 mM的类似物对未处理细胞的脱羧酶活性均无显著直接抑制作用。因此，推测类似物对处理细胞中这些酶的影响主要是由调节机制介导的。在这方面，BESm优于BES，因为鸟氨酸和腺苷甲硫氨酸脱羧酶活性均受到抑制。鉴于其独特的活性，BESm似乎具有作为抗增殖剂以及作为研究多胺途径特别是腺苷甲硫氨酸脱羧酶调节的实验探针的潜力。
