Youle R J, Newton D, Wu Y N, Gadina M, Rybak S M
Biochemistry Section, NINDS, NIH, Bethesda, MD 20892.
Crit Rev Ther Drug Carrier Syst. 1993;10(1):1-28.
Ribonucleases serve as cytotoxic agents during host defense and physiological cell death pathways. In bacteria, higher plants, and mammals, ribonucleases appear to bind cells, enter the cytosol where they degrade RNA, and kill the target cell. This process functions in interstrain competition in bacteria, in the death of incompatible pollen in higher plants, and likely plays a role in the antiparasitic and anticancer activity of eosinophils in man. One can alter the target cell specificity of RNases by coupling them to new cell-binding domains. Chemically coupling RNases to new binding moieties or fusing RNase genes to antibody genes results in chimeric molecules with specified cell-type cytotoxicity. Thus, one can target one's own host defense cytotoxins to select cell populations. This allows the use of human proteins, instead of plant and bacterial toxins, in the construction of immunotoxins. RNases also can be engineered to kill cells by cytosolic expression or to kill viruses by packaging into viruses. Engineering RNases into cell-type-specific cytotoxins may result in a new class of therapeutic reagents. We review a number of interesting physiological cell cytotoxicity pathways utilizing RNases and then describe the recent results on engineering RNases for therapeutic use.
核糖核酸酶在宿主防御和生理性细胞死亡途径中作为细胞毒性剂发挥作用。在细菌、高等植物和哺乳动物中，核糖核酸酶似乎会与细胞结合，进入胞质溶胶，在其中降解RNA，并杀死靶细胞。这一过程在细菌的菌株间竞争、高等植物中不亲和花粉的死亡中起作用，并且可能在人类嗜酸性粒细胞的抗寄生虫和抗癌活性中发挥作用。通过将核糖核酸酶与新的细胞结合结构域偶联，可以改变核糖核酸酶的靶细胞特异性。将核糖核酸酶化学偶联到新的结合部分或将核糖核酸酶基因与抗体基因融合，会产生具有特定细胞类型细胞毒性的嵌合分子。因此，可以将自身的宿主防御细胞毒素靶向特定的细胞群体。这使得在构建免疫毒素时可以使用人类蛋白质，而不是植物和细菌毒素。核糖核酸酶还可以通过胞质表达来设计用于杀死细胞，或者通过包装到病毒中来杀死病毒。将核糖核酸酶设计成细胞类型特异性细胞毒素可能会产生一类新的治疗试剂。我们综述了一些利用核糖核酸酶的有趣的生理性细胞细胞毒性途径，然后描述了将核糖核酸酶用于治疗用途的最新研究结果。
