Blood, 1 February 2004, Vol. 103, No. 3, pp. 836-842.
Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-07-2307.
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HEMATOPOIESIS
A potential therapeutic role for small nonpeptidyl compounds that mimic human granulocyte colony-stimulating factor
Kouji Kusano,
Shinji Ebara,
Koichi Tachibana,
Tadahiro Nishimura,
Susumu Sato,
Tomoaki Kuwaki, and
Tadayoshi Taniyama
From the Central Research Laboratories, SSP, Chiba, Japan; Pharmaceutical Development Laboratories, Kirin Brewery, Gunma, Japan; and Laboratory of Bacterial Infection and Immunity, Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation of bone marrow granulocytic progenitor cells and promotes their differentiation into granulocytes. G-CSF is therefore an important component of immune defense against pathogenic microorganisms: recombinant human G-CSF (rhG-CSF) is used to treat patients with a variety of neutropenias. In the present study, we screened approximately 10 000 small nonpeptidyl compounds and found 3 small compounds that mimic G-CSF in several in vitro and in vivo assays. These compounds induced G-CSF–dependent proliferation, but had no effect on interleukin-3–dependent, interleukin-2–dependent, interleukin-10–dependent, thrombopoietin (TPO)–dependent, or erythropoietin (EPO)–dependent proliferation. Each compound induced the phosphorylation of signal transducers and activators of transcription–3 (STAT3) and mitogen-activated protein kinase (MAPK) in a G-CSF–dependent cell line and in human neutrophils. In addition, these compounds induced hematopoietic colony formation from primary rat bone marrow cells in vitro. When subcutaneously injected into normal rats, they caused an increase in peripheral blood neutrophil counts. Furthermore, when they were administered to cyclophosphamide-induced neutropenic rats, blood neutrophil levels increased and remained elevated up to day 8. We therefore suggest that these small nonpeptidyl compounds mimic the activity of G-CSF and may be useful in the treatment of neutropenic patients.
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