REGULATORY AND ANTIPROLIFERATIVE EFFECTS OF N-ALKYLATED POLYAMINE ANALOGS IN HUMAN AND HAMSTER PANCREATIC ADENOCARCINOMA CELL-LINES
REGULATORY AND ANTIPROLIFERATIVE EFFECTS OF N-ALKYLATED POLYAMINE ANALOGS IN HUMAN AND HAMSTER PANCREATIC ADENOCARCINOMA CELL-LINES
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DOI：
10.1007/bf00686309
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发表时间：
1992-07-01
影响因子：
3
通讯作者：
LIBBY, PR
中科院分区：
文献类型：
--
作者：
CHANG, BK;BERGERON, RJ;LIBBY, PR
N-烷基化多胺类似物已显示在几种肿瘤模型中发挥抗增殖作用，其中双乙基衍生物通过下调多胺生物合成酶而发挥对多胺的最大抑制作用。胰腺癌由于其对常规治疗的固有抗性而在临床和实验上都提出了挑战，这导致其具有所有癌症中最差的5年生存率。我们以前已经表明，N1，N-12-双-（乙基）精胺（BESPM）是更有效的多胺酶抑制剂α-二氟甲基鸟氨酸（DFMO）对胰腺癌细胞系。在本研究中，我们比较了两种N-烷基化多胺类似物，N1，N-14-双（乙基）高精胺（BEHSPM）和N1，N-11-双（乙基）去甲精胺（BENSPM）在两个人胰腺导管腺癌细胞系，PANC-1（低分化）和BxPC-3（中度分化），并在WD PaCa（高分化导管）仓鼠细胞系的生化和抗增殖作用。BENSPM在人胰腺癌细胞系中显示出更大的抗增殖活性，而BEHSPM在仓鼠细胞系中更有效。BEHSPM和BENSPM均抑制主要生物合成酶鸟氨酸脱羧酶和S-腺苷甲硫氨酸脱羧酶的活性。然而，在人细胞系中多胺耗竭的诱导对于BENSPM仅是适度的，对于BEHSPM是最小的，这表明这些类似物的实质性抗增殖活性可能来自多胺耗竭以外的机制。用BENSPM处理后观察到的稍微更大的多胺消耗被认为是由于其对亚精胺/精胺N1-乙酰转移酶的显著诱导。BENSPM的生物化学和抗增殖活性使其成为进一步临床前和临床开发的有吸引力的药物，特别是在胰腺癌中。
N-Alkylated polyamine analogues have been shown to exert antiproliferative effects in several tumor models, with the bis-ethyl derivatives exerting the greatest suppression of polyamines by virtue of down-regulation of the polyamine biosynthetic enzymes. Pancreatic adenocarcinoma presents a challenge both clinically and experimentally due to its inherent resistance to conventional therapy, which results in its having the worst 5-year survival rate of all cancers. We have previously shown that N1,N-12-bis-(ethyl)spermine (BESPM) is much more potent than the polyamine enzyme inhibitor alpha-difluoromethylomithine (DFMO) against pancreatic adenocarcinoma cell lines. In the present study, we compared the biochemical and antiproliferative effects of two N-alkylated polyamine analogues, N1,N-14-bis(ethyl)homospermine (BEHSPM) and N1,N-11-bis(ethyl)norspermine (BENSPM) in two human pancreatic ductal adenocarcinoma cell lines, PANC-1 (poorly differentiated) and BxPC-3 (moderately well-differentiated), and in the WD PaCa (well-differentiated ductal) hamster cell line. BENSPM displayed greater antiproliferative activity in the human pancreatic cancer cell lines, whereas BEHSPM was more potent in the hamster cell line. Both BEHSPM and BENSPM suppress the activity of the major biosynthetic enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase. However, the induction of polyamine depletion in the human cell lines was only modest for BENSPM and minimal for BEHSPM, which suggests that the substantial antiproliferative activity of these analogues may result from mechanisms other than polyamine depletion. The somewhat greater polyamine depletion seen following treatment with BENSPM is thought to result from its striking induction of spermidine/spermine N1-acetyltransferase. The biochemical and antiproliferative activity of BENSPM makes it an attractive agent for further preclinical and clinical development, especially in pancreatic cancer.