Colangelo Donato, Osella Domenico
Dipartimento di Scienze dell'Ambiente e della Vita, Università degli Studi del Piemonte Orientale "A. Avogadro", Spalto Marengo 33, I-15100 Alessandria, Italy.
Curr Med Chem. 2005;12(26):3091-102. doi: 10.2174/092986705774933416.
Telomerase is a ribonucleoprotein polymerase that maintains the length of telomeric DNA by adding hexameric units (TTAGGG) to the ends of the chromosomes. This mechanism prevents replicative senescence, thus conferring unlimited proliferative potential to cells. Telomerase reactivation has been detected in most human tumour tissue, indicating that the enzyme may be useful as a specific tumour marker. The inhibition of telomerase causes a progressive and critical reduction of telomeres, leading to a potent signal for the blockage of cell proliferation and the induction of apoptosis. Since normal somatic cells lack telomerase activity, the anti-telomerase approach is highly specific for tumour cells and metastases. Prolonged treatment is required before enzyme deactivation causes the telomeres to be shortened enough to induce senescence and apoptosis. Therefore, the drugs employed in anti-telomerase therapy should be of only moderate non-specific cytotoxicity. Certain cis-Pt(II)-complexes have recently been shown to be effective inhibitors of telomerase in both cell-free and in vitro assays, most likely by targeting the nucleobases of the RNA component of the enzyme.
端粒酶是一种核糖核蛋白聚合酶，它通过在染色体末端添加六聚体单元（TTAGGG）来维持端粒DNA的长度。这种机制可防止复制性衰老，从而赋予细胞无限增殖潜能。在大多数人类肿瘤组织中都检测到了端粒酶的重新激活，这表明该酶可能作为一种特异性肿瘤标志物。抑制端粒酶会导致端粒进行性且关键的缩短，从而产生一个强有力的信号，阻止细胞增殖并诱导细胞凋亡。由于正常体细胞缺乏端粒酶活性，抗端粒酶方法对肿瘤细胞和转移瘤具有高度特异性。在酶失活导致端粒缩短到足以诱导衰老和凋亡之前，需要进行长期治疗。因此，用于抗端粒酶治疗的药物应仅具有适度的非特异性细胞毒性。最近已证明某些顺铂（II）配合物在无细胞和体外试验中都是有效的端粒酶抑制剂，最有可能是通过靶向该酶RNA成分的核碱基来实现的。
