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 glutamate pyruvate transaminase (GPT) and blood urea nitrogen (BUN) and had a significant immunosuppressive effect on B- and T-lymphocytes. The present analysis and comparison of the biodistribution and systemic/organ toxicity associated with RIP injection suggest a possible in vivo mechanism of action of PAP-1 and PAP-S and identify several limitations in the clinical use of these two toxins and RTA. When administered intravenously, PAP-1 and PAP-S consistently accumulated in kidneys and induced histologically documented damage to kidney and liver, with a LD50 of 3.3 mg/kg and 1.6 mg/kg for PAP-1 and PAP-S, respectively. In mice injected with PAP-S after chlorpromazine (CPZ) administration, GPT 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 inhibited the expansion of anti-sheep red blood cells (SRBC) antibody-forming cells and the production of anti-SRBC antibody levels, although PAP-S showed the most potent activity. Despite the immunosuppressive activity, all toxins were highly immunogenic.
Benigni
F
F
Division of Experimental Oncology E, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Canevari
S
S
Gadina
M
M
Adobati
E
E
Ferreri
A J
AJ
Di Celle
E F
EF
Comolli
R
R
Colnaghi
M I
MI
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001806:Blood Urea Nitrogen; D004353:Drug Evaluation, Preclinical; D005260:Female; D018796:Immunoconjugates; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009699:N-Glycosyl Hydrolases; D000073718:Pancreatitis-Associated Proteins; D010940:Plant Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D054789:Ribosome Inactivating Proteins, Type 1; D012270:Ribosomes / Q000187:drug effects*; D012276:Ricin / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014018:Tissue Distribution
D018796:Immunoconjugates; D000073718:Pancreatitis-Associated Proteins; D010940:Plant Proteins; C000612141:REG3A protein, human; D054789:Ribosome Inactivating Proteins, Type 1; D012276:Ricin; D000410:Alanine Transaminase; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein