Porter C W, Ganis B, Libby P R, Bergeron R J
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263.
Cancer Res. 1991 Jul 15;51(14):3715-20.
The polyamine analogue, N1,N12-bis(ethyl(-spermine (BESPM), is known to suppress ornithine and S-adenosylmethionine decarboxylase levels, deplete intracellular polyamine pools, and inhibit cell growth. Among human melanoma cell lines, MALME-3 cells were found to be typically sensitive to the antiproliferative activity of the BESPM, whereas LOX cells were atypically insensitive to the analogue. A comparison of polyamine-related parameters revealed that the most differentially altered activity between the 2 BESPM-treated cell lines was that of spermidine/spermine N1-acetyltransferase (SSAT), which increased from 50 pmol/min/mg to greater than 10,000 pmol/min/mg in MALME-3 cells and from 16 pmol/min/mg to only 120 pmol/min/mg in LOX cells over 48 h. The basis for the large difference seems to be related to increased enzyme synthesis in both cell lines coupled with differences in prolongation of SSAT half-life (greater than 12 h in MALME-3 cells versus 1.6 h in LOX cells) after BESPM treatment. In MALME-3 cells, SSAT accumulation was found to be differentially modulated by the BESPM homologues, N1,N11-bis-(ethyl)norspermine and N1,N14-bis-(ethyl)homospermine, which were 5-fold more and 9-fold less effective, respectively, than BESPM in increasing SSAT but similar in analogue uptake and effects on polyamine biosynthesis and cell growth inhibition. Treatment of MALME-3 cells with BESPM resulted in an accumulation of N-acetylspermidine in cells and the enhanced excretion of putrescine, spermidine, and N-acetylspermidine into the medium. The relationship between SSAT induction and growth sensitivity was deduced to be a possible function of increased excretion of acetylated polyamines leading to enhanced polyamine pool depletion. The data suggest that, in cell types in which it occurs, unusually high increases in SSAT activity may serve as a determinant of growth sensitivity to bis-ethyl spermine analogues or, alternatively, as a target for appropriately designed chemotherapeutic strategies.
多胺类似物N1,N12 - 双（乙基）- 亚精胺（BESPM）已知可抑制鸟氨酸和S - 腺苷甲硫氨酸脱羧酶水平，耗尽细胞内多胺池，并抑制细胞生长。在人类黑色素瘤细胞系中，发现MALME - 3细胞对BESPM的抗增殖活性通常敏感，而LOX细胞对该类似物则表现出非典型的不敏感。对多胺相关参数的比较显示，在两种经BESPM处理的细胞系之间，最具差异改变的活性是亚精胺/精胺N1 - 乙酰基转移酶（SSAT）的活性，在48小时内，其在MALME - 3细胞中从50 pmol/分钟/毫克增加到大于10,000 pmol/分钟/毫克，而在LOX细胞中从16 pmol/分钟/毫克仅增加到120 pmol/分钟/毫克。这种巨大差异的基础似乎与两种细胞系中酶合成的增加以及BESPM处理后SSAT半衰期延长的差异有关（MALME - 3细胞中大于12小时，而LOX细胞中为1.6小时）。在MALME - 3细胞中，发现BESPM同系物N1,N11 - 双（乙基）去甲亚精胺和N1,N14 - 双（乙基）高亚精胺对SSAT的积累有不同的调节作用，它们在增加SSAT方面的效果分别比BESPM高5倍和低9倍，但在类似物摄取以及对多胺生物合成和细胞生长抑制的影响方面相似。用BESPM处理MALME - 3细胞导致细胞内N - 乙酰亚精胺的积累以及腐胺、亚精胺和N - 乙酰亚精胺向培养基中的排泄增加。SSAT诱导与生长敏感性之间的关系被推断为乙酰化多胺排泄增加导致多胺池耗尽增强的一种可能作用。数据表明，在发生这种情况的细胞类型中，SSAT活性异常高的增加可能是对双乙基亚精胺类似物生长敏感性的一个决定因素，或者作为适当设计的化疗策略的一个靶点。
