Aragona M, Maisano R, Panetta S, Giudice A, Morelli M, La Torre I, La Torre F
Unita Operativa di Oncologia Medica, Universita di Messina, Messina, Italy.
Int J Oncol. 2000 Nov;17(5):981-9. doi: 10.3892/ijo.17.5.981.
Normal somatic cells have a finite number of divisions, a limited capacity to proliferate. Human telomeres, the long DNA TTAGGG repeats at the ends of chromosomes, are considered a molecular clock marker. The gradual and progressive telomere shortening at each replicative cycle is associated, through the activation of pRB and p53 pathways and genomic instability, to the replicative senescence, a non-dividing state and widespread cell death. Activation of telomere maintenance [telomerase; or alternative lengthening of telomeres mechanisms (ALT), or other adaptive responses] can revert this program. Although not completely known, several mechanisms and modulating agents may be able to up and down-regulate telomere length and its maintenance. Chemopreventive therapies for the up-regulation of telomerase activity, able to prolong the life of cell cultures in a phenotypically youthful state, could have important applications in research and medicine. On the contrary the therapeutic down-regulation of telomerase activity may be used in cancer therapy. Telomerase expression per se is not oncogenic, but telomere shortening and maintenance seem to be crucial events in tumor formation. Thus a particular focus has been pointed out relatively to the immortalization of normal or potential pre-cancerous cells. With the extension of life span the probability to get in contact with carcinogens increases, genetic instability, oncogene activation and/or onco-suppressor gene inactivation (i.e. p53, pRB, ras): the cancer transformation can be then induced in predisposed cells, depending on their genetic context, by the activation of telomere maintenance. Pharmacological intervention may be able to modulate the rate of living, by increasing life span of few specific target cells, or decreasing it in proliferating
正常体细胞的分裂次数有限，增殖能力也有限。人类端粒是染色体末端的长DNA TTAGGG重复序列，被认为是一种分子时钟标记。在每个复制周期中，端粒逐渐且持续缩短，通过pRB和p53通路的激活以及基因组不稳定性，与复制性衰老相关，复制性衰老即一种非分裂状态和广泛的细胞死亡。端粒维持机制（端粒酶；或端粒替代延长机制（ALT），或其他适应性反应）的激活可以逆转这一程序。尽管尚未完全明确，但几种机制和调节因子可能能够上调和下调端粒长度及其维持。上调端粒酶活性的化学预防疗法能够使细胞培养物在表型年轻的状态下延长寿命，这在研究和医学中可能具有重要应用。相反，下调端粒酶活性的疗法可用于癌症治疗。端粒酶表达本身并不致癌，但端粒缩短和维持似乎是肿瘤形成中的关键事件。因此，对于正常或潜在癌前细胞的永生化，已经有了特别的关注。随着寿命的延长，接触致癌物的可能性增加，出现基因不稳定、癌基因激活和/或抑癌基因失活（如p53、pRB、ras）：然后，根据其遗传背景，通过激活端粒维持，可在易感细胞中诱导癌症转化。药物干预或许能够通过延长少数特定靶细胞的寿命或缩短增殖中的<癌细胞和癌前细胞>的寿命来调节生命速率。由于人类机体中大量细胞的未知状态，使用治疗药物延长人类寿命是否安全呢？
