Preijers F W
Department of Hematology, University Hospital St. Radboud, Nijmegen, The Netherlands.
Leuk Lymphoma. 1993 Mar;9(4-5):293-304. doi: 10.3109/10428199309148526.
The use of chemotherapeutic drugs in combination with bone marrow transplantation to treat cancer patients has markedly improved the disease-free survival and cure rate. Part of the tumor cells, however, can escape from therapy due to resistance. Tumor-specific delivery of toxins that do not interfere with conventional drugs and are not cell cycle dependent seems to be a reasonable approach to overcome this problem. Natural ribosome-inhibiting-proteins (RIPs) from plants, bacteria and fungi which are extremely toxic inhibitors of protein synthesis are isolated and coupled to monoclonal antibodies (MoAbs) and receptor-specific ligands, immunotoxins (ITs), to fulfil this purpose. ITs are very suitable to eliminate malignant cells in vitro and in vivo. RIPs contain two or three active sites: a binding site which can be absent in a part of the RIPs and can be replaced by the MoAb; a translocation site that facilitates transport into the cytosol after internalization, and a cytotoxic site that enzymatically inhibits protein synthesis. Binding site containing toxins induce strong nonspecific cytotoxicity when coupled to MoAbs. Recent developments in recombinant DNA techniques enable genetic elimination of the binding site to reduce nonspecific cytotoxicity of these toxins. In this review the structures and mechanisms of action of RIPs as well as factors that influence cytotoxicity of immunotoxins are discussed. Moreover the problems dealing with in vivo application of ITs such as blood clearance by instability of the IT and hepatic entrapment, and production of antibodies directed against MoAb and toxin are reviewed.
将化疗药物与骨髓移植联合用于治疗癌症患者，已显著提高了无病生存率和治愈率。然而，部分肿瘤细胞可因耐药性而逃避治疗。递送不干扰传统药物且不依赖细胞周期的毒素以实现肿瘤特异性靶向，似乎是解决这一问题的合理方法。从植物、细菌和真菌中分离出的天然核糖体抑制蛋白（RIPs）是极具毒性的蛋白质合成抑制剂，将其与单克隆抗体（MoAbs）及受体特异性配体偶联形成免疫毒素（ITs），以达到这一目的。ITs非常适合在体外和体内清除恶性细胞。RIPs含有两个或三个活性位点：一个结合位点，部分RIPs中可能不存在该位点，可被单克隆抗体替代；一个易位位点，有助于内化后转运至胞质溶胶；一个细胞毒性位点，可酶促抑制蛋白质合成。与单克隆抗体偶联时，含有结合位点的毒素会诱导强烈的非特异性细胞毒性。重组DNA技术的最新进展能够通过基因手段消除结合位点，以降低这些毒素的非特异性细胞毒性。在这篇综述中，将讨论RIPs的结构和作用机制以及影响免疫毒素细胞毒性的因素。此外，还将综述与ITs体内应用相关的问题，如ITs因稳定性导致的血液清除、肝脏截留，以及针对单克隆抗体和毒素产生的抗体。
