Richardson D R, Tran E H, Ponka P
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Blood. 1995 Dec 1;86(11):4295-306.
Numerous studies have suggested that iron (Fe) chelators such as desferrioxamine (DFO) may be useful antitumor agents (Blatt and Stitely, Cancer Res 47:1749, 1987; Becton and Bryles, Cancer Res 48:7189, 1988). Recent work with several analogues of the lipophilic Fe chelator, pyridoxal isonicotinoyl hydrazone (PIH), indicate that some of these ligands are considerably more efficient than DFO both in terms of their Fe chelation efficacy and at preventing 3H-thymidine incorporation by neuroblastoma (NB) cells (Richardson and Ponka, J Lab Clin Med 124:660, 1994). Considering this fact, the present study was designed to test the antiproliferative effect of a wide range of PIH analogues to identify the most active compounds. A total of 36 ligands have been examined that were synthesized by condensation of three types of aromatic aldehydes (pyridoxal, salicylaldehyde, and 2-hydroxy-1-naphthyladehyde) with a range of acid hydrazides. The effects of these chelators were assessed using the human NB cell line, SK-N-MC. Although PIH was far more effective than DFO at preventing Fe uptake from transferrin, it was less effective than DFO at preventing cellular proliferation (DFO ID50 = 22 mumol/L; PIH ID50 = 75 mumol/L). In contrast, 14 PIH analogues were far more efficient than DFO at preventing proliferation (ID50 = 1 to 7 mumol/L) and may have potential as antitumor agents. The most effective compounds were those hydrazones derived from 2-hydroxy-1-naphthylaldehyde. Most of the PIH analogues were considerably more effective than DFO at both preventing 59Fe uptake from 59Fe-transferrin and in mobilizing 59Fe from prelabeled NB cells. In addition, a linear relationship between Fe chelation efficacy and antiproliferative activity was found only for hydrazones derived from salicylaldehyde. Apart from gallium (Ga) nitrate having an antiproliferative effect by itself, this metal potentiated the antiproliferative effect of PIH but not that of DFO. Spectrophotometric studies showed that PIH could chelate Ga, and it can be suggested that, like the PIH-Fe complex that donates Fe to reticulocytes (Ponka et al, Biochim Biophys Acta 718:151, 1982), the PIH-Ga complex may efficiently bestow Ga to NB cells. The results suggest that analogues of PIH deserve further vigorous investigation because they may be useful therapeutic agents for the treatment of cancer.
大量研究表明，去铁胺（DFO）等铁（Fe）螯合剂可能是有用的抗肿瘤药物（布拉特和斯蒂利特，《癌症研究》47:1749，1987；贝克顿和布赖尔斯，《癌症研究》48:7189，1988）。最近对亲脂性铁螯合剂吡啶醛异烟酰腙（PIH）的几种类似物的研究表明，其中一些配体在铁螯合功效以及阻止神经母细胞瘤（NB）细胞掺入3H-胸腺嘧啶方面比DFO效率高得多（理查森和庞卡，《实验与临床检验医学杂志》124:660，1994）。考虑到这一事实，本研究旨在测试多种PIH类似物的抗增殖作用，以鉴定最具活性的化合物。总共检测了36种通过三种芳香醛（吡啶醛、水杨醛和2-羟基-1-萘甲醛）与一系列酰肼缩合合成的配体。使用人NB细胞系SK-N-MC评估了这些螯合剂的作用。尽管PIH在阻止铁从转铁蛋白摄取方面远比DFO有效，但在阻止细胞增殖方面不如DFO有效（DFO的半数抑制浓度ID50 = 22 μmol/L；PIH的ID50 = 75 μmol/L）。相比之下，14种PIH类似物在阻止增殖方面远比DFO有效（ID50 = 1至7 μmol/L），可能具有作为抗肿瘤药物的潜力。最有效的化合物是那些源自2-羟基-1-萘甲醛的腙。大多数PIH类似物在阻止59Fe从59Fe-转铁蛋白摄取以及从预先标记的NB细胞中动员59Fe方面远比DFO有效。此外，仅在源自水杨醛的腙中发现铁螯合功效与抗增殖活性之间存在线性关系。除了硝酸镓本身具有抗增殖作用外，这种金属增强了PIH的抗增殖作用，但没有增强DFO的抗增殖作用。分光光度研究表明PIH可以螯合镓，可以推测，就像将铁捐赠给网织红细胞的PIH-Fe复合物（庞卡等人，《生物化学与生物物理学报》718:151，1982）一样，PIH-Ga复合物可能有效地将镓赋予NB细胞。结果表明，PIH类似物值得进一步深入研究，因为它们可能是治疗癌症的有用治疗剂。
