PRECLINICAL EVALUATION OF THE RIBOSOME-INACTIVATING PROTEINS PAP-1, PAP-S AND RTA IN MICE

In a preclinical mouse model the plant ribosome-inactivating proteins (RIPs) pokeweed antiviral proteins PAP-1, and PAP-S and ricin A-chain (RTA) induced a pathological elevation of serum concentrations of glut amate pyruvate transaminase (GPT) and blood urea nitrogen (BUN) and ha d a significant immunosuppressive effect on B- and T-lymphocytes. The present analysis and comparison of the biodistribution and systemic/or gan toxicity associated with RIP injection suggest a possible in vivo mechanism of action of PAP-1 and PAP-S and identify several limitation s in the clinical use of these two toxins and RTA. When administered i ntravenously, PAP-1 and PAP-S consistently accumulated in kidneys and induced histologically documented damage to kidney and liver, with a L D(50) Of 3.3 mg/kg and 1.6 mg/kg for PAP-I and PAP-S, respectively. In mice injected with PAP-S after chlorpromazine (CPZ) administration, G PT levels returned to normal between 24 and 72 h after toxin injection , while the BUN levels remained elevated. Mortality of the animals was delayed but all mice eventually succumbed. All the three toxins inhib ited the expansion of anti-sheep red blood cells (SRBC) antibody-formi ng cells and the production of anti-SRBC antibody levels, although PAP -S showed the most potent activity. Despite the immunosuppressive acti vity, all toxins were highly immunogenic.