Quantitative analysis of protein synthesis inhibition by transferrin-toxin conjugates

A mathematical model was developed which relates the time and concentration dependence of protein synthesis inhibition of an immunotoxin to the properties of the targeting agent and the conjugated toxin. The role of the targeting agent and that of the toxin in determining the cytotoxicity were separ...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1994-12, Vol.54 (24), p.6387-6394
Main Authors: YAZDI, P. T, MURPHY, R. M
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Cell Membrane - metabolism
General aspects
HeLa Cells - metabolism
Humans
Immunotoxins - metabolism
Kinetics
Medical sciences
Melanoma - metabolism
Models, Biological
Models, Theoretical
Neoplasm Proteins - metabolism
Pharmacology. Drug treatments
Plant Proteins - metabolism
Ribosome Inactivating Proteins, Type 1
Ribosomes - metabolism
Transferrin - metabolism
Tumor Cells, Cultured
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Summary:A mathematical model was developed which relates the time and concentration dependence of protein synthesis inhibition of an immunotoxin to the properties of the targeting agent and the conjugated toxin. The role of the targeting agent and that of the toxin in determining the cytotoxicity were separated in this model by describing protein synthesis inhibition as a function of a cellular trafficking variable, which is calculated from the trafficking parameters of the targeting agent, and a protein synthesis inhibition constant, which is a property of the translocation and enzymatic rate constants of the toxin. Transferrin cellular trafficking parameters were determined experimentally for HeLa and SK-MEL-2 cells. Protein synthesis inhibition of transferrin-gelonin and transferrin-CRM107 conjugates in both cell lines was measured as a function of time and concentration. Analysis of the data showed that the model was a good representation of the experimental results, and correctly explained cell line differences in sensitivity to transferrin-toxin conjugates. The translocation rate constant for transferrin-CRM107 was approximately 3000 times greater than that for transferrin-gelonin. The model may be useful in understanding the factors that influence immunotoxin efficacy and in designing more lethal immunotoxins.
ISSN:0008-5472
1538-7445