Differential activation of the endogenous leukotriene biosynthesis by two different preparations of granulocyte-macrophage colony-stimulating factor in healthy volunteers.
Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM-CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.
Medizinische Klinik III, Ludwig-Maximilians Universität, München, Germany.
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Denzlinger
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Tetzloff
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Gerhartz
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Pokorny
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Sagebiel
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Haberl
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Wilmanns
D000328:Adult; D000818:Animals; D016466:CHO Cells / Q000378:metabolism; D006224:Cricetinae; D004926:Escherichia coli / Q000378:metabolism; D006031:Glycosylation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007958:Leukocyte Count; D017999:Leukotriene E4 / Q000031:analogs & derivatives; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013189:SRS-A / Q000031:analogs & derivatives / Q000652:urine
D015289:Leukotrienes; D011994:Recombinant Proteins; D013189:SRS-A; D017999:Leukotriene E4; C047630:N-acetylleukotriene E4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor