文章：

多胺和癌症：旧的分子，新的认识

Polyamines and cancer: old molecules, new understanding

原文发布日期：2004-10-01

DOI: 10.1038/nrc1454

类型: Review Article

开放获取: 否

要点：

1. Polyamines are naturally occurring organic cations found in plants, animals and microbes. They are formed by the enzymatic decarboxylation of the amino acids ornithine or arginine.
2. Ornithine decarboxylase (ODC) is the first enzyme in the polyamine synthesis pathway in mammals and is the target for difluoromethylornithine (DFMO), a substrate analogue and specific inhibitor that irreversibly inactivates ODC when it binds to the active site of the enzyme.
3. ODC and several other polyamine metabolic proteins are essential for normal cell and tissue functions, including growth, development and tissue repair. ODC and polyamine content are increased in many cancers arising from epithelial tissues, such as the skin and colon.
4. Polyamines exert their effects in eukaryotic cells in part by regulating specific gene expression.
5. In murine and human colonic mucosal tissue, ODC is negatively regulated by the adenomatous polyposis coli (APC) tumour-suppressor gene. APC is mutated or deleted in the germline of people with familial adenomatous polyposis (FAP), a genetic syndrome associated with a high risk of colon cancer. APC is also mutated or deleted in somatic colon epithelial cells in most sporadic, or non-genetic, forms of colon cancer.
6. Loss of APC function causes an increase in ODC activity and polyamine biosynthesis, and tumour formation in Apc^Min/+ mice, a murine model of human FAP. Treatment of Apc^Min/+ mice with DFMO suppresses intestinal tumour formation.
7. Several non-steroidal anti-inflammatory drugs (NSAIDs), the use of which is associated with decreased risk of epithelial cancers, activate the transcription of spermidine/spermine N¹-acetyltransferase, the first enzyme in the polyamine catabolic pathway. Experimental studies indicate that combinations of DFMO and NSAIDs are potent inhibitors of colon and intestinal cancer development in murine models.
8. Clinical studies have shown that DFMO is well tolerated and can prevent the development of precancerous lesions in the skin. Several large randomized trials involving the skin, colon and other organ sites are underway.

要点翻译：

1. 多胺是存在于植物、动物和微生物中的天然有机阳离子。它们通过氨基酸鸟氨酸或精氨酸的酶促脱羧作用形成。
2. 鸟氨酸脱羧酶（ODC）是哺乳动物多胺合成途径中的第一个酶，也是二氟甲基鸟氨酸（DFMO）的作用靶点。DFMO作为一种底物类似物和特异性抑制剂，当其结合到ODC的活性位点时，会不可逆地灭活该酶。
3. ODC和其他几种多胺代谢蛋白对正常细胞和组织功能至关重要，包括生长、发育和组织修复。在上皮组织（如皮肤和结肠）来源的多种癌症中，ODC和多胺含量会升高。
4. 多胺在真核细胞中部分通过调节特定基因表达来发挥作用。
5. 在小鼠和人类的结肠黏膜组织中，ODC受到腺瘤性结肠息肉病（APC）肿瘤抑制基因的负向调控。在患有家族性腺瘤性息肉病（FAP）——一种与结肠癌高风险相关的遗传综合征——的人群的种系中，APC基因会发生突变或缺失。在大多数散发性（非遗传性）结肠癌中，结肠上皮细胞的体细胞APC基因也会发生突变或缺失。
6. APC功能丧失会导致ODC活性和多胺生物合成增加，并在ApcMin/+小鼠（一种模拟人类FAP的小鼠模型）中引发肿瘤形成。使用DFMO治疗ApcMin/+小鼠可抑制肠道肿瘤的形成。
7. 几种非甾体抗炎药（NSAIDs）能够激活多胺分解代谢途径中的第一个酶——亚精胺/精胺N1-乙酰转移酶的转录，这类药物的使用与上皮性癌症风险降低相关。实验研究表明，在小鼠模型中，DFMO与NSAIDs的联合使用能有效抑制结肠癌和肠道癌的发展。
8. 临床研究表明，DFMO耐受性良好，并能预防皮肤癌前病变的发展。目前正在针对皮肤、结肠及其他器官部位进行多项大规模随机试验。

英文摘要：

The amino-acid-derived polyamines have long been associated with cell growth and cancer, and specific oncogenes and tumour-suppressor genes regulate polyamine metabolism. Inhibition of polyamine synthesis has proven to be generally ineffective as an anticancer strategy in clinical trials, but it is a potent cancer chemoprevention strategy in preclinical studies. Clinical trials, with well-defined goals, are now underway to evaluate the chemopreventive efficacy of inhibitors of polyamine synthesis in a range of tissues.

摘要翻译： 

氨基酸来源的多胺一直与细胞生长和癌症相关，特定的癌基因和抑癌基因调控多胺代谢。抑制多胺合成在临床试验中被证明作为抗癌策略通常无效，但在临床前研究中却是一种强有力的癌症化学预防策略。目前，具有明确目标的临床试验正在进行中，以评估多胺合成抑制剂在多种组织中的化学预防效果。

原文链接：

Polyamines and cancer: old molecules, new understanding