Toxicity, distribution and elimination of the cancerostatic lectins abrin and ricin after parenteral injection into mice

Fodstad, Øystein; Olsnes, Sjur; Pihl, Alexander

doi:10.1038/bjc.1976.187

Cited by 116 publications

(63 citation statements)

References 10 publications

(3 reference statements)

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“…Since several studies have demonstrated the antitumour properties of ricin (Lin et al, 1970;Fodstad et al, 1976Fodstad et al, , 1977Fodstad & Pihl, 1978), preliminary experiments were carried out to evaluate its effect on M-MSV-induced tumour growth. Tumour-bearing irradiated mice, receiving M-MSV in the rear footpad 5 to 6 days previously, were injected i.v.…”

Section: Antitumour Activity Of Ricin-treated T-lymphocyte Transfermentioning

confidence: 99%

Temporary inhibition of Moloney-murine sarcoma virus (M-MSV) induced-tumours by adoptive transfer of ricin-treated T-lymphocytes

Cerundolo¹,

Zanovello²,

McIntosh³

et al. 1987

Br J Cancer

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Summary The potential use of tumour-specific T-lymphocytes loaded with ricin in cell targeting experiments was investigated. Moloney-murine sarcoma virus (M-MSV)-specific T-lymphocytes, obtained in mass mixed leucocyte-tumour cell culture (MLTC) and a M-MSV-specific cytotoxic T-lymphocyte (CTL) clone, were incubated with 125I-labelled ricin in order to evaluate toxin uptake and release. The internalized ricin (4.5 x 10-"7 mol and 6.5 x 10-17 mol per 102 MLTC and CTL clone cells, respectively) was released rapidly during the first 30min following treatment, and at a constant but slower rate over the next few hours. The cytotoxic activity of ricin-treated cells evaluated against antigen-related target cells, in a short term incubation "Cr release assay, was unaffected during the first 30min after treatment but decreased with time over the next few hours. However, the growth of antigen related as well as of unrelated tumour cells was strongly inhibited by the addition of ricin-treated cells to the culture system, thus indicating that released ricin is toxic for untreated target cells.The in vivo localization pattern of ricin-treated radiolabelled MLTC cells was found to be comparable with that of untreated cells 1 h after i.v. injection into syngeneic sublethally irradiated mice. After 6 h, however, more radiolabel was recovered from the liver of mice receiving ricin-treated MLTC cells.Ricin-treated M-MSV-specific T-lymphocytes were injected i.v. into tumour bearing sublethally irradiated mice. A temporary tumour growth inhibition (up to 6 days) was achieved following transfer of low doses of ricin-treated MLTC or CTL clone cells (1 x 106 and 0.5 x 106, respectively). In contrast, in M-MSV injected control mice, receiving only free toxin (from 5 to 20ng) or untreated tumour-specific effector cell tumours grew progressively. The therapeutic effect was apparently specific since the injection of ricin-treated alloreactive T-lymphocytes did not influence tumour growth.These results suggest that M-MSV-specific T-lymphocytes loaded with ricin can deliver toxin to the target tumour mass and have a transient therapeutic effect.

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Section: Antitumour Activity Of Ricin-treated T-lymphocyte Transfermentioning

confidence: 99%

Temporary inhibition of Moloney-murine sarcoma virus (M-MSV) induced-tumours by adoptive transfer of ricin-treated T-lymphocytes

Cerundolo¹,

Zanovello²,

McIntosh³

et al. 1987

Br J Cancer

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“…When injected intravenously into rats or mice, rich rapidly accumulates in the liver and, to a lesser extent, in the spleen [5] wise be cleared from the bloodstream in animals and prompted us to devise ways of modifying the carbohydrate side chains in the toxin to prevent hepatic recognition. A previous attempt by Simeral et al [8] to destroy the carbohydrate in ricin using sodium metaperiodate resulted in virtually complete loss of toxicity.…”

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confidence: 99%

Modification of the carbohydrate in ricin with metaperiodate — cyanoborohydride mixtures

Thorpe

Detre

Foxwell

et al. 1985

European Journal of Biochemistry

108

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Attempts to target antibody-ricin conjugates (immunotoxins) to designated cell types in vivo may be thwarted by their rapid clearance by hepatic reticuloendothelial cells which have receptors that recognise oligosaccharide side chains on the toxin. The B-chain of ricin contains high mannose type oligosaccharides and the A-chain contains a complex unit (GlcNAc)2-Fuc-Xyl-(Man)4-6, all of which potentially could be recognised by the reticuloendothelial system.Treatment of ricin with a mixture of sodium metaperiodate and sodium cyanoborohydride at pH 3.5 resulted in oxidative cleavage of the carbohydrates and reduction of the aldehyde groups thus formed to primary alcohols. By conducting the modification procedure at acidic pH, both the possibility of Schiff s base formation between the aldehyde groups and amino groups in the protein and the possibility of non-specific oxidation of amino acids were minimised. The extent of the carbohydrate modification depended on the duration of treatment, resulting maximally in the destruction of 13 of the 18 mannose residues and of all xylose and fucose.The toxicity of the modified toxin to cells in culture declined by up to 90% as the carbohydrate was destroyed. This was not due to a reduced ability of the B-chain to bind to cells or of the A-chain to inactivate ribosomes. In contrast to the in vitro results, the toxicity of the modified toxin to mice and rats was elevated by up to fourfold. The modification greatly reduced the clearance of the toxin by non-parenchymal cells in the liver and prevented the damage to hepatic Kupffer and sinusoidal cells and to the red pulp of the spleen that is inflicted by the native toxin. The elevated toxicity to animals appears to be because the modified toxin evades the reticuloendothelial system and persists in the bloodstream for longer periods, thus resulting in lethal damage to vital tissues in the animal at lower dosage.The results suggest that immunotoxins prepared from modified ricin would not be readily cleared by the reticuloendothelial system and so be more effective at killing their target cells.Attempts have been made in several laboratories to target ricin to designated cell types in animals by linking it to specific antibodies (reviewed in [l -31).Ricin, the toxin from the castor bean, is a glycoprotein comprising two polypeptide chains, A and B, joined by a disulphide bond. The B-chain binds to galactose-containing glycoproteins and glycolipids on cell surfaces and the A-chain then penetrates the membrane (probably from an endocytic vesicle) and kills the cell by inactivating ribosomes (reviewed in 141).When injected intravenously into rats or mice, rich rapidly accumulates in the liver and, to a lesser extent, in the spleen [5] wise be cleared from the bloodstream in animals and prompted us to devise ways of modifying the carbohydrate side chains in the toxin to prevent hepatic recognition. A previous attempt by Simeral et al. [8] to destroy the carbohydrate in ricin using sodium metaperiodate resulted in virtually complete ...

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“…Cells resistant to abrin and ricin were isolated as surviving clones of X-ray irradiated HeLa. cells grown in the presence of 1 pg/ml of abrin or ricin [7].…”

Section: Methodsmentioning

confidence: 99%

Properties and action mechanism of the toxic lectin modeccin: Interaction with cell lines resistant to modeccin, abrin, and ricin

Olsnes

Sandvig²,

Eiklid

et al. 1978

J Supramol Struct

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The toxic lectin modeccin, which inhibits protein synthesis in eukaryotic cells, is cleaved upon treatment with 2-mercaptoethanol into two peptide chains which move in polyacrylamide gels at rates corresponding to molecular weights 28,000 and 38,000. After reduction, the toxin loses its effect on cells, while its ability to inhibit cell-free protein synthesis increases. Like abrin and ricin it inhibits protein synthesis by inactivating the 60S ribosomal subunits. Modeccin binds to surface receptors containing terminal galactose residues. Competition experiments with various glycoproteins indicate that the modeccin receptors are different from the abrin receptors. In addition, they were present on HeLa cells in much smaller numbers. Moreover, mutant lines resistant to abrin and ricin were not resistant to modeccin and vice-versa. The toxin resistance of various mutant cell lines could not be accounted for by a reduced number of binding sites on cells. The data are consistent with the view that the cells possess different populations of binding sites with differences in ability to facilitate the uptake of the toxins and that in the resistant lines the most active receptors have been reduced or eliminated.

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Toxicity, distribution and elimination of the cancerostatic lectins abrin and ricin after parenteral injection into mice

Cited by 116 publications

References 10 publications

Temporary inhibition of Moloney-murine sarcoma virus (M-MSV) induced-tumours by adoptive transfer of ricin-treated T-lymphocytes

Temporary inhibition of Moloney-murine sarcoma virus (M-MSV) induced-tumours by adoptive transfer of ricin-treated T-lymphocytes

Modification of the carbohydrate in ricin with metaperiodate — cyanoborohydride mixtures

Properties and action mechanism of the toxic lectin modeccin: Interaction with cell lines resistant to modeccin, abrin, and ricin

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