AZT: An Old Drug with New Perspectives
AZT: An Old Drug with New Perspectives
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DOI：
10.2174/157488408783329913
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Bozzi, Argante
中科院分区：
文献类型：
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作者：
D'Andrea, Gabriele;Brisdelli, Fabrizia;Bozzi, Argante
当艾滋病毒/艾滋病在1980年代初作为一种主要的新病毒疾病出现时，抗病毒研究的科学已经取得了很大的进展。第一个有效的抗病毒化合物（AZT，叠氮胸苷，齐多夫定）已经在筛选的化合物库中，并迅速被报道为逆转录病毒，包括艾滋病毒的特异性抑制剂。由于AZT在HIV治疗中的关键作用，本文综述了AZT诱导的最已知的效应-其中一些是毒副作用-AZT是一种仍用于HIV感染患者的联合治疗的药物。在毒副作用中，已经报道了严重的骨髓毒性，其表现为贫血、中性粒细胞减少和铁质沉着，并且是由血红素和珠蛋白合成的抑制以及铁供应的一般紊乱引起的。在这方面，我们证明，虽然AZT和它的单磷酸化衍生物AZTMP不能螯合铁，三磷酸形式AZTTP显示出显着的能力，从转铁蛋白中去除铁。此外，我们以前已经证明，AZT暴露的K562细胞显示出位于细胞膜上的转铁蛋白受体的增加，而不影响其生物合成，但减缓其内吞途径。有趣的是，文献数据报告了AZT对糖基化反应的损害。事实上，我们已经表明，AZT处理的K562细胞表现出减少的蛋白质和脂质的唾液酸化，并强烈抑制，（2 - 8）唾液酸转移酶的活性，而（1 - 4）半乳糖基转移酶和半乳糖苷酶的活性显着增加。这些后一种观察结果可能具有临床意义，因为细胞内和细胞表面碳水化合物表达和组成的改变通常与几种疾病相关。然而，与其他作者关于AZT作为植物和细菌毒素活性抑制剂的先前报道相反，我们已经证明AZT不仅不抑制皂草素毒性，而且甚至增加了这种植物毒素对K562细胞的细胞毒性活性。此外，审查启发了潜在的利用AZT作为一种工具，在蛋白质组学，因为在最近几年，几个基因响应这种药物已被确定在不同的细胞系。我们已经表明，在AZT暴露的K562细胞中，两种蛋白质（PDI-A3和sthatmin）的过表达，以及另外两种蛋白质（HSP-60和SOD 1）的完全抑制。目前，我们正在研究上述报道的改变是否是AZT处理培养细胞的一般特征，或者它们代表特定细胞系的特有特征。最后，本文回顾了一些旨在提高AZT血浆水平及其在人体所有器官中的生物利用度的新方法，以提高其针对HIV感染的治疗效果。这些新的可能性，即叠氮胸苷前药策略、叠氮胸苷透皮给药和靶向脑给药，尚未用于人类，但正在进行实验研究。
The science of antiviral research was well advanced when HIV/AIDS appeared as a major new virus disease in the early 1980s. The first effective antiviral compound (AZT, azidothymidine, zidovudine) was already among the library of compounds screened and was promptly reported to be a specific inhibitor of retroviruses, including HIV. Due to the pivotal role of AZT in HIV treatment, this review summarizes the most known effects -some of which are toxic side effects- induced by AZT a drug which is still used in the combined therapy of HIV-infected patients. Among the toxic side effects, a severe bone marrow toxicity manifested as anemia, neutropenia and siderosis, and caused by inhibition of heme and globin synthesis together with a general derangement of iron supply, have been reported. In this regard, we proved that while AZT and its monophosphorylated derivative AZTMP were unable to chelate iron, the triphosphate form AZTTP displayed a significant capacity to remove iron from transferrin. Moreover, we have previously demonstrated that AZT-exposed K562 cells showed an increase of transferrin receptors located on the cell membrane without affecting their biosynthesis, but slowing down their endocytotic pathway. Interestingly, literature data report the impairement of glycosylation reactions by AZT. Indeed, we have shown that AZT-treated K562 cells exhibited a reduced sialylation of proteins and lipids, and a strong inhibition of,(2 8) sialyltransferase activity while,(1 4) galactosyltransferase and galactosidase activities were significantly increased. These latter observations could be of clinical relevance since alterations of intracellular and cell surface carbohydrate expression and composition, often are associated with several diseases. However, contrarily to previous reports by other authors on AZT as an inhibitor of plant and bacterial toxins activity, we have demonstrated that AZT not only did not inhibit saporin toxicity, but even increased the cytotoxic activity of this plant toxin on K562 cells. Furthermore, the review enlightens the potential utilization of AZT as a tool in proteomics since in the recent years several genes responding to this drug have been identified in different cell lines. We have shown, for the first time, an over-expression of two proteins (PDI-A3 and sthatmin), and a full repression of two others (HSP-60 and SOD1) in AZT-exposed K562 cells. At present, we are investigating if the above reported alterations are a general feature of AZT-treatment of cultured cells, or they represent a peculiar characteristic of a specific cell line. Finally, the paper reviews a number of novel methodologies aimed at enhancing the AZT plasma levels and its bioavailability in all human organs in order to improve its therapeutic efficacy against HIV infection. These new possibilities, namely the AZT prodrug strategy, the AZT transdermal delivery and the targeted brain delivery, are yet not in use for humans but they are under experimental studies.