Datta Abhik, Bellon Marcia, Sinha-Datta Uma, Bazarbachi Ali, Lepelletier Yves, Canioni Danielle, Waldmann Thomas A, Hermine Olivier, Nicot Christophe
Department of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, 3025 Wahl Hall West, 3901 Rainbow Blvd, Kansas City, 66160, USA.
Blood. 2006 Aug 1;108(3):1021-9. doi: 10.1182/blood-2006-01-0067. Epub 2006 Mar 28.
The antiviral thymidine analog azidothymidine (AZT) is used to treat several virus-associated human cancers. However, to date the mechanism of AZT action remains unclear and thus, reasons for treatment failure are unknown. Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of poor prognosis. Here, we report that enduring AZT treatment of T-cell leukemia virus I-infected cells, in vitro and in vivo in ATL patients, results in inhibition of telomerase activity, progressive telomere shortening, and increased p14(ARF) expression. In turn, this elicits stabilization and reactivation of the tumor suppressor p53-dependent transcription, increased expression of the cyclin-dependent kinase inhibitor p21(Waf1), and accumulation of p27(kip1), thereby inducing cellular senescence and tumor cell death. While ATL patients carrying a wild-type p53 enter remission following treatment with AZT, those with a mutated p53 did not respond, and patients' disease relapse was associated with the selection of a tumor clone carrying mutated inactive p53.
抗病毒的胸腺嘧啶核苷类似物叠氮胸苷（AZT）被用于治疗几种与病毒相关的人类癌症。然而，迄今为止，AZT的作用机制仍不清楚，因此，治疗失败的原因也不明。成人T细胞白血病/淋巴瘤（ATL）是一种预后不良的侵袭性恶性肿瘤。在此，我们报告，在体外以及对ATL患者进行体内试验时，对感染I型T细胞白血病病毒的细胞进行持续的AZT治疗，会导致端粒酶活性受到抑制、端粒逐渐缩短以及p14（ARF）表达增加。相应地，这会引发肿瘤抑制因子p53依赖转录的稳定和重新激活、细胞周期蛋白依赖性激酶抑制剂p21（Waf1）的表达增加以及p27（kip1）的积累，从而诱导细胞衰老和肿瘤细胞死亡。携带野生型p53的ATL患者在接受AZT治疗后病情缓解，而携带突变型p53的患者则无反应，并且患者疾病复发与携带突变的无活性p53的肿瘤克隆的选择有关。
