Arnold Ulrich
Martin-Luther University Halle-Wittenberg, Institute of Biochemistry and Biotechnology, Kurt-Mothes-Str. 3, 06120 Halle, Germany.
Curr Pharm Biotechnol. 2008 Jun;9(3):161-8. doi: 10.2174/138920108784567263.
By virtue of their RNA degrading catalytic activity, ribonucleases are potentially cytotoxic. For the application of these enzymes as therapeutics, however, they have to overcome several obstacles whose interplay is not yet fully understood. Ribonucleases with a basic pI are not only able to interact with the (negatively charged) cellular membrane but they are also distinctively selective for tumor cells. After the (endocytotic) uptake into the cell and release into the cytosol from the endosomes where they have to resist the attack by proteases, they face the cytosolic ribonuclease inhibitor. Only if they are able to evade the tight binding to the inhibitor (or if enough ribonuclease molecules enter the cell to neutralize the inhibitor protein) they are able to attack their target RNA, for which a sufficient ribonucleolytic activity is indispensable. Each of these steps can turn into an insurmountable hurdle spoiling the cytotoxic potential of these enzymes. In the present review I will summarize the status quo of the knowledge on the mechanisms and their interdependence as well as to develop strategies to overcome possible limitations.
由于其RNA降解催化活性，核糖核酸酶具有潜在的细胞毒性。然而，对于将这些酶用作治疗剂而言，它们必须克服几个障碍，而这些障碍之间的相互作用尚未完全明了。具有碱性pI的核糖核酸酶不仅能够与（带负电荷的）细胞膜相互作用，而且对肿瘤细胞具有独特的选择性。在通过内吞作用进入细胞并从内体释放到细胞质后，它们必须抵抗蛋白酶的攻击，此时它们会遇到细胞质核糖核酸酶抑制剂。只有当它们能够避免与抑制剂紧密结合（或者如果足够数量的核糖核酸酶分子进入细胞以中和抑制剂蛋白）时，它们才能够攻击其靶RNA，而足够的核糖核酸水解活性是必不可少的。这些步骤中的每一个都可能成为阻碍这些酶细胞毒性潜力发挥的不可逾越的障碍。在本综述中，我将总结关于这些机制及其相互依赖性的知识现状，并制定克服可能限制的策略。
