Hatse S, De Clercq E, Balzarini J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Biochem Pharmacol. 1999 Aug 15;58(4):539-55. doi: 10.1016/s0006-2952(99)00035-0.
Transformed cells are characterized by imbalances in metabolic routes. In particular, different key enzymes of nucleotide metabolism and DNA biosynthesis, such as CTP synthetase, thymidylate synthase, dihydrofolate reductase, IMP dehydrogenase, ribonucleotide reductase, DNA polymerase, and DNA methyltransferase, are markedly up-regulated in certain tumor cells. Together with the concomitant down-modulation of the purine and pyrimidine degradation enzymes, the increased anabolic propensity supports the excessive proliferation of transformed cells. However, many types of cancer cells have maintained the ability to differentiate terminally into mature, non-proliferating cells not only in response to physiological receptor ligands, such as retinoic acid, vitamin D metabolites, and cytokines, but also following exposure to a wide variety of non-physiological agents such as antimetabolites. Interestingly, induction of tumor cell differentiation is often associated with reversal of the transformation-related enzyme deregulations. An important class of differentiating compounds comprises the antimetabolites of purine and pyrimidine nucleotide metabolism and nucleic acid synthesis, the majority being structural analogs of natural nucleosides. The CTP synthetase inhibitors cyclopentenylcytosine and 3-deazauridine, the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine, the dihydrofolate reductase inhibitor methotrexate, the IMP dehydrogenase inhibitors tiazofurin, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and mycophenolic acid, the ribonucleotide reductase inhibitors hydroxyurea and deferoxamine, and the DNA polymerase inhibitors ara-C, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and aphidicolin, as well as several nucleoside analogs perturbing the DNA methylation pattern, have been found to induce tumor cell differentiation through impairment of DNA synthesis and/or function. Thus, by selectively targeting those anabolic enzymes that contribute to the neoplastic behavior of cancer cells, the normal cellular differentiation program may be reactivated and the malignant phenotype suppressed.
转化细胞的特征是代谢途径失衡。特别是，核苷酸代谢和DNA生物合成的不同关键酶，如CTP合成酶、胸苷酸合成酶、二氢叶酸还原酶、肌苷酸脱氢酶、核糖核苷酸还原酶、DNA聚合酶和DNA甲基转移酶，在某些肿瘤细胞中显著上调。伴随着嘌呤和嘧啶降解酶的下调，合成代谢倾向的增加支持了转化细胞的过度增殖。然而，许多类型的癌细胞不仅能够在生理受体配体（如视黄酸、维生素D代谢物和细胞因子）的作用下，而且在接触多种非生理剂（如抗代谢物）后，保持终末分化为成熟、非增殖细胞的能力。有趣的是，肿瘤细胞分化的诱导通常与转化相关酶失调的逆转有关。一类重要的分化化合物包括嘌呤和嘧啶核苷酸代谢以及核酸合成的抗代谢物，其中大多数是天然核苷的结构类似物。CTP合成酶抑制剂环戊烯基胞嘧啶和3-去氮尿苷、胸苷酸合成酶抑制剂5-氟-2'-脱氧尿苷、二氢叶酸还原酶抑制剂甲氨蝶呤、肌苷酸脱氢酶抑制剂替拉扎明、利巴韦林、5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺（EICAR）和霉酚酸、核糖核苷酸还原酶抑制剂羟基脲和去铁胺、DNA聚合酶抑制剂阿糖胞苷、9-(2-膦酰甲氧基乙基)腺嘌呤（PMEA）和阿非迪霉素，以及几种扰乱DNA甲基化模式的核苷类似物，已被发现可通过损害DNA合成和/或功能来诱导肿瘤细胞分化。因此，通过选择性地靶向那些导致癌细胞肿瘤行为的合成代谢酶，可以重新激活正常的细胞分化程序并抑制恶性表型。
