Influence of varying doses of granulocyte-macrophage colony-stimulating factor on pharmacokinetics and antibody-dependent cellular cytotoxicity.
Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) is used in immunotherapy for correction of neutropoenia. The optimal dose for activation of immune functions and the pharmacokinetics following repeated administrations is less analysed in depth. In this study, the pharmacokinetics and the effects on haematological functions and antibody-dependent cellular cytotoxicity (ADCC) were analysed in 50 patients with metastatic colorectal carcinoma receiving monoclonal antibody based therapy in combination with Escherichia coli-derived GM-CSF (molgramostim) administered s.c. once daily for 10 days every month over a period of 4 months. Thirty-three patients received a GM-CSF dose of 200-250 microg/m(2)/day. Seventeen patients received GM-CSF doses varying between 65 and 325 microg/m(2)/day in the different treatment cycles. Serum GM-CSF concentration was measured (ELISA) before and 3-4 h after (peak serum concentration) GM-CSF administration days 1, 5 and 10. Prior to therapy, GM-CSF was not detectable in serum. Following repeated daily administrations, the peak serum concentration of GM-CSF gradually decreased on days 5 and 10 compared to day 1 (P < 0.05). During a 10-day treatment cycle, the total number of leukocytes, neutrophils, eosinophils, monocytes and lymphocytes increased. A dose-dependent increment in total white blood cell count and neutrophils was observed. The total numbers of GM-CSF receptor (alpha-subunit) expressing cells (granulocytes and monocytes) increased significantly during treatment while a transient decline in expression intensity was observed at day 5, suggesting a receptor-mediated removal of GM-CSF as a mechanism for the elimination of GM-CSF from circulation. ADCC of peripheral mononuclear cells was decreased at day 10 compared to baseline. An inverse correlation between the dose and ADCC was noted. The data might indicate that high doses of GM-CSF may have a negative impact on ADCC.
Liljefors
Maria
M
Department of Oncology and Pathology (Radiumhemmet), Cancer Centre Karolinska, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
Nilsson
Bo
B
Mellstedt
Håkan
H
Frödin
Jan-Erik
JE
D000328:Adult; D000368:Aged; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage; D007958:Leukocyte Count; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D016898:Interferon-alpha; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C082430:molgramostim; D005472:Fluorouracil