A potential therapeutic role for small nonpeptidyl compounds that mimic human granulocyte colony-stimulating factor.
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.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003114:Colony-Forming Units Assay; D004353:Drug Evaluation, Preclinical; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018716:Molecular Mimicry; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D016179:Granulocyte Colony-Stimulating Factor