TY - JOUR
T1 - Preclinical evaluation of the ribosome-inactivating proteins PAP-1, PAP-S and RTA in mice
AU - Benigni, Fabio
AU - Canevari, Silvana
AU - Gadina, Massimo
AU - Adobati, Elena
AU - Ferreri, Andrés JoséMaria
AU - Ferraris Di Celle, Elena
AU - Comolli, Roberto
AU - Colnaghi, Maria Ines
PY - 1995
Y1 - 1995
N2 - 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.
AB - 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.
KW - blood urea nitrogen
KW - chlorpromazine
KW - glutamate pyruvate transaminase
KW - immunosuppression
KW - immunotoxin
KW - ribosome-inactivating protein
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U2 - 10.1016/0192-0561(95)00068-D
DO - 10.1016/0192-0561(95)00068-D
M3 - Article
C2 - 8707448
AN - SCOPUS:0028811624
VL - 17
SP - 829
EP - 839
JO - International Journal of Immunopharmacology
JF - International Journal of Immunopharmacology
SN - 0192-0561
IS - 10
ER -