Seiler Nikolaus
Laboratory of Nutritional Oncology, INSERM U-392, Institut de Recherche contre les Cancers de l'Appareil Digestif, 1, place de l'hôpital, B.P. 426, 67091 Strasbourg, France.
Curr Drug Targets. 2003 Oct;4(7):537-64. doi: 10.2174/1389450033490885.
As soon as the natural polyamines (PAs), putrescine (Put), spermidine (Spd) and spermine (Spm), were recognized as ubiquitous constituents of eukaryotic cells, their involvement in growth-related processes attracted particular interest. The high activities of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) in rapidly growing tissues and cells, particularly in tumour cells, suggested PA biosynthesis as a target for antineoplastic therapy. In the course of the years selective inhibitors have been developed for literally all enzymes of PA metabolism. Some became important as tools in the elucidation of the PA metabolic system, but only few of them were efficient as inhibitors of tumour growth. A major reason for the inefficacy of selective enzyme inhibitors as anticancer drugs is the sophistication of the system, which regulates intracellular PA pools. Selective blockade of a single enzyme induces changes of metabolism and transport, which compensate for the deficit. The selective impairment of tumour growth is in addition hampered by the ubiquitous occurrence of the PAs, their importance in normal functions of nearly all mammalian cells, and the ability or the mammalian organism to utilize exogenous (gastrointestinal) PAs. Among the inhibitors of PA-related enzymes, the ODC inactivator (R, S)-2-(difluoromethyl)ornithine (DFMO) became most famous. Although it was disappointing in most therapeutic attempts to use it as single drug, it has--based on its low toxicity--considerable potential in cancer chemoprevention, and it turned out to be a highly efficient anti-trypanosome agent. Very likely DFMO is suitable to improve the efficacy of some of the current cytotoxic drugs, and it may allow one to create new therapies in combination with other PA-directed drugs. Some of the less selective enzyme inhibitors, particularly those, which inhibit two or more enzymes of PA metabolism, appear to have had a chance to become practically useful, but they have not been developed energetically. Disregarding DFMO, the AdoMetDC inhibitor SAM486A is the only compound for which clinical trials were published. The future of this drug is unclear at present; presumably phase III clinical trials have been discontinued. One of the lessons that had to be learned from the work on selective enzyme inhibitors was that PA metabolism is a much more difficult target, than has been expected on the basis of the simplicity of the PA structures, and the simple reactions involved in their biosynthesis. In order to inhibit tumour growth several reactions or regulatory functions of PA metabolism have to be impaired at the same time. Recent efforts devoted to the development new types of anticancer drugs, which are based on the perturbation of PA metabolism by structural analogues of the natural PAs, take this message into account. These approaches are the topic of the 2nd part of this overview.
一旦天然多胺（PAs），即腐胺（Put）、亚精胺（Spd）和精胺（Spm），被确认为真核细胞中普遍存在的成分，它们在与生长相关过程中的作用就引起了特别关注。鸟氨酸脱羧酶（ODC）和S-腺苷甲硫氨酸脱羧酶（AdoMetDC）在快速生长的组织和细胞，特别是肿瘤细胞中的高活性，表明多胺生物合成可作为抗肿瘤治疗的靶点。多年来，人们实际上已经为多胺代谢的所有酶开发了选择性抑制剂。其中一些作为阐明多胺代谢系统的工具变得很重要，但只有少数作为肿瘤生长抑制剂有效。选择性酶抑制剂作为抗癌药物无效的一个主要原因是该系统的复杂性，它调节细胞内多胺池。单一酶的选择性阻断会引起代谢和转运的变化，从而弥补这种不足。肿瘤生长的选择性受损还受到多胺普遍存在、它们在几乎所有哺乳动物细胞正常功能中的重要性以及哺乳动物机体利用外源性（胃肠道）多胺的能力的阻碍。在多胺相关酶的抑制剂中，ODC灭活剂（R，S）-2-（二氟甲基）鸟氨酸（DFMO）最为著名。尽管在大多数将其作为单一药物的治疗尝试中令人失望，但基于其低毒性，它在癌症化学预防方面具有相当大的潜力，并且被证明是一种高效的抗锥虫剂。很可能DFMO适合提高一些现有细胞毒性药物的疗效，并且它可能允许人们与其他针对多胺的药物联合创造新的疗法。一些选择性较低的酶抑制剂，特别是那些抑制多胺代谢的两种或更多种酶的抑制剂，似乎有机会变得实际有用，但它们尚未得到大力开发。除了DFMO，AdoMetDC抑制剂SAM486A是唯一发表了临床试验的化合物。目前这种药物的前景尚不明朗；推测III期临床试验已经停止。从选择性酶抑制剂的研究工作中必须吸取的一个教训是，多胺代谢是一个比基于多胺结构的简单性及其生物合成中涉及的简单反应所预期的要困难得多的靶点。为了抑制肿瘤生长，多胺代谢的几个反应或调节功能必须同时受到损害。最近致力于开发新型抗癌药物的努力考虑到了这一点，这些药物基于天然多胺的结构类似物对多胺代谢的干扰。这些方法是本综述第二部分的主题。
