Comparison of the pharmacokinetics and hepatotoxic effects of saporin and ricin A-chain immunotoxins on murine liver parenchymal cells

D. C. Blakey, D. N. Skilleter, R. J. Price, G. J. Watson, L. I. Hart, D. R. Newell, P. E. Thorpe

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Immunotoxins containing the ribosome-inactivating protein, saporin, are very effective antitumor agents but are highly toxic to mice. They induce severe necrotic lesions in the liver parenchyma of the recipients. Such extensive damage to the liver parenchyma is not observed with ricin A-chain immunotoxins even at 5-fold higher dosage. The hepatotoxicity of the saporin immunotoxins was found in the present study to arise from a combination of two effects. First, saporin and saporin immunotoxins were 30- and 6-fold more toxic to primary cultures of mouse liver parenchymal cells than were ricin A-chain and ricin A-chain immunotoxins, respectively. This was despite the fact that the cells bound 4- to 5-fold less saporin or saporin immunotoxins than ricin A-chain or ricin A-chain immunotoxins. The binding of ricin A-chain and its immunotoxin to the cells was mediated through the carbohydrate residues present on the A-chain whereas saporin is not glycosylated and thus must bind to other sites on the cell surface which result in transport of saporin relatively efficiently to the cytosol. The second reason for the hepatotoxic action of the saporin immunotoxin was that it had a longer blood half-life (t( 1/2 ) α = 1.1 h; t( 1/2 ) β = 17.1 h) than the ricin A-chain immunotoxin (t( 1/2 ) = 0.52 h; t 1/2 β = 9.7 h). Analyses using a two-compartment pharmacokinetic model showed that the two immunotoxins broke down in vivo to give free antibody at a similar rate (t( 1/2 ) = 10-12 h) but that the ricin A-chain immunotoxin was eliminated 11 times more rapidly than the saporin immunotoxin by routes other than breakdown. It was calculated that, in mice given median lethal dose of saporin immunotoxin, the blood levels of immunotoxin remained above the concentration that killed 50% of parenchymal cells in vitro for more than 48 h. In mice given a median lethal dose of ricin A-chain immunotoxin, the blood levels fell below the concentration that was toxic to parenchymal cells in vitro within 4 h. The longer blood half-life of the saporin immunotoxin may also explain our previous finding that it had antitumor activity superior to that of a ricin A-chain immunotoxin in mice.

Original languageEnglish (US)
Pages (from-to)7072-7078
Number of pages7
JournalCancer Research
Volume48
Issue number24 I
StatePublished - 1988

Fingerprint

Ricin
Immunotoxins
Pharmacokinetics
Liver
Poisons
saporin
Half-Life
Ribosome Inactivating Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Blakey, D. C., Skilleter, D. N., Price, R. J., Watson, G. J., Hart, L. I., Newell, D. R., & Thorpe, P. E. (1988). Comparison of the pharmacokinetics and hepatotoxic effects of saporin and ricin A-chain immunotoxins on murine liver parenchymal cells. Cancer Research, 48(24 I), 7072-7078.

Comparison of the pharmacokinetics and hepatotoxic effects of saporin and ricin A-chain immunotoxins on murine liver parenchymal cells. / Blakey, D. C.; Skilleter, D. N.; Price, R. J.; Watson, G. J.; Hart, L. I.; Newell, D. R.; Thorpe, P. E.

In: Cancer Research, Vol. 48, No. 24 I, 1988, p. 7072-7078.

Research output: Contribution to journalArticle

Blakey, DC, Skilleter, DN, Price, RJ, Watson, GJ, Hart, LI, Newell, DR & Thorpe, PE 1988, 'Comparison of the pharmacokinetics and hepatotoxic effects of saporin and ricin A-chain immunotoxins on murine liver parenchymal cells', Cancer Research, vol. 48, no. 24 I, pp. 7072-7078.
Blakey DC, Skilleter DN, Price RJ, Watson GJ, Hart LI, Newell DR et al. Comparison of the pharmacokinetics and hepatotoxic effects of saporin and ricin A-chain immunotoxins on murine liver parenchymal cells. Cancer Research. 1988;48(24 I):7072-7078.
Blakey, D. C. ; Skilleter, D. N. ; Price, R. J. ; Watson, G. J. ; Hart, L. I. ; Newell, D. R. ; Thorpe, P. E. / Comparison of the pharmacokinetics and hepatotoxic effects of saporin and ricin A-chain immunotoxins on murine liver parenchymal cells. In: Cancer Research. 1988 ; Vol. 48, No. 24 I. pp. 7072-7078.
@article{23e1562e39f04b90af8f01b9891f80bd,
title = "Comparison of the pharmacokinetics and hepatotoxic effects of saporin and ricin A-chain immunotoxins on murine liver parenchymal cells",
abstract = "Immunotoxins containing the ribosome-inactivating protein, saporin, are very effective antitumor agents but are highly toxic to mice. They induce severe necrotic lesions in the liver parenchyma of the recipients. Such extensive damage to the liver parenchyma is not observed with ricin A-chain immunotoxins even at 5-fold higher dosage. The hepatotoxicity of the saporin immunotoxins was found in the present study to arise from a combination of two effects. First, saporin and saporin immunotoxins were 30- and 6-fold more toxic to primary cultures of mouse liver parenchymal cells than were ricin A-chain and ricin A-chain immunotoxins, respectively. This was despite the fact that the cells bound 4- to 5-fold less saporin or saporin immunotoxins than ricin A-chain or ricin A-chain immunotoxins. The binding of ricin A-chain and its immunotoxin to the cells was mediated through the carbohydrate residues present on the A-chain whereas saporin is not glycosylated and thus must bind to other sites on the cell surface which result in transport of saporin relatively efficiently to the cytosol. The second reason for the hepatotoxic action of the saporin immunotoxin was that it had a longer blood half-life (t( 1/2 ) α = 1.1 h; t( 1/2 ) β = 17.1 h) than the ricin A-chain immunotoxin (t( 1/2 ) = 0.52 h; t 1/2 β = 9.7 h). Analyses using a two-compartment pharmacokinetic model showed that the two immunotoxins broke down in vivo to give free antibody at a similar rate (t( 1/2 ) = 10-12 h) but that the ricin A-chain immunotoxin was eliminated 11 times more rapidly than the saporin immunotoxin by routes other than breakdown. It was calculated that, in mice given median lethal dose of saporin immunotoxin, the blood levels of immunotoxin remained above the concentration that killed 50{\%} of parenchymal cells in vitro for more than 48 h. In mice given a median lethal dose of ricin A-chain immunotoxin, the blood levels fell below the concentration that was toxic to parenchymal cells in vitro within 4 h. The longer blood half-life of the saporin immunotoxin may also explain our previous finding that it had antitumor activity superior to that of a ricin A-chain immunotoxin in mice.",
author = "Blakey, {D. C.} and Skilleter, {D. N.} and Price, {R. J.} and Watson, {G. J.} and Hart, {L. I.} and Newell, {D. R.} and Thorpe, {P. E.}",
year = "1988",
language = "English (US)",
volume = "48",
pages = "7072--7078",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "24 I",

}

TY - JOUR

T1 - Comparison of the pharmacokinetics and hepatotoxic effects of saporin and ricin A-chain immunotoxins on murine liver parenchymal cells

AU - Blakey, D. C.

AU - Skilleter, D. N.

AU - Price, R. J.

AU - Watson, G. J.

AU - Hart, L. I.

AU - Newell, D. R.

AU - Thorpe, P. E.

PY - 1988

Y1 - 1988

N2 - Immunotoxins containing the ribosome-inactivating protein, saporin, are very effective antitumor agents but are highly toxic to mice. They induce severe necrotic lesions in the liver parenchyma of the recipients. Such extensive damage to the liver parenchyma is not observed with ricin A-chain immunotoxins even at 5-fold higher dosage. The hepatotoxicity of the saporin immunotoxins was found in the present study to arise from a combination of two effects. First, saporin and saporin immunotoxins were 30- and 6-fold more toxic to primary cultures of mouse liver parenchymal cells than were ricin A-chain and ricin A-chain immunotoxins, respectively. This was despite the fact that the cells bound 4- to 5-fold less saporin or saporin immunotoxins than ricin A-chain or ricin A-chain immunotoxins. The binding of ricin A-chain and its immunotoxin to the cells was mediated through the carbohydrate residues present on the A-chain whereas saporin is not glycosylated and thus must bind to other sites on the cell surface which result in transport of saporin relatively efficiently to the cytosol. The second reason for the hepatotoxic action of the saporin immunotoxin was that it had a longer blood half-life (t( 1/2 ) α = 1.1 h; t( 1/2 ) β = 17.1 h) than the ricin A-chain immunotoxin (t( 1/2 ) = 0.52 h; t 1/2 β = 9.7 h). Analyses using a two-compartment pharmacokinetic model showed that the two immunotoxins broke down in vivo to give free antibody at a similar rate (t( 1/2 ) = 10-12 h) but that the ricin A-chain immunotoxin was eliminated 11 times more rapidly than the saporin immunotoxin by routes other than breakdown. It was calculated that, in mice given median lethal dose of saporin immunotoxin, the blood levels of immunotoxin remained above the concentration that killed 50% of parenchymal cells in vitro for more than 48 h. In mice given a median lethal dose of ricin A-chain immunotoxin, the blood levels fell below the concentration that was toxic to parenchymal cells in vitro within 4 h. The longer blood half-life of the saporin immunotoxin may also explain our previous finding that it had antitumor activity superior to that of a ricin A-chain immunotoxin in mice.

AB - Immunotoxins containing the ribosome-inactivating protein, saporin, are very effective antitumor agents but are highly toxic to mice. They induce severe necrotic lesions in the liver parenchyma of the recipients. Such extensive damage to the liver parenchyma is not observed with ricin A-chain immunotoxins even at 5-fold higher dosage. The hepatotoxicity of the saporin immunotoxins was found in the present study to arise from a combination of two effects. First, saporin and saporin immunotoxins were 30- and 6-fold more toxic to primary cultures of mouse liver parenchymal cells than were ricin A-chain and ricin A-chain immunotoxins, respectively. This was despite the fact that the cells bound 4- to 5-fold less saporin or saporin immunotoxins than ricin A-chain or ricin A-chain immunotoxins. The binding of ricin A-chain and its immunotoxin to the cells was mediated through the carbohydrate residues present on the A-chain whereas saporin is not glycosylated and thus must bind to other sites on the cell surface which result in transport of saporin relatively efficiently to the cytosol. The second reason for the hepatotoxic action of the saporin immunotoxin was that it had a longer blood half-life (t( 1/2 ) α = 1.1 h; t( 1/2 ) β = 17.1 h) than the ricin A-chain immunotoxin (t( 1/2 ) = 0.52 h; t 1/2 β = 9.7 h). Analyses using a two-compartment pharmacokinetic model showed that the two immunotoxins broke down in vivo to give free antibody at a similar rate (t( 1/2 ) = 10-12 h) but that the ricin A-chain immunotoxin was eliminated 11 times more rapidly than the saporin immunotoxin by routes other than breakdown. It was calculated that, in mice given median lethal dose of saporin immunotoxin, the blood levels of immunotoxin remained above the concentration that killed 50% of parenchymal cells in vitro for more than 48 h. In mice given a median lethal dose of ricin A-chain immunotoxin, the blood levels fell below the concentration that was toxic to parenchymal cells in vitro within 4 h. The longer blood half-life of the saporin immunotoxin may also explain our previous finding that it had antitumor activity superior to that of a ricin A-chain immunotoxin in mice.

UR - http://www.scopus.com/inward/record.url?scp=0024265081&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024265081&partnerID=8YFLogxK

M3 - Article

C2 - 3263899

AN - SCOPUS:0024265081

VL - 48

SP - 7072

EP - 7078

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 24 I

ER -