Synergistic effect of granulocyte colony-stimulating factor and drugs elevating extracellular adenosine on neutrophil production in mice.
Experimental evidence suggests that the activation of purinoceptors by extracellular adenosine can modulate proliferation and/or differentiation of hematopoietic cells. The present study was undertaken to investigate the potential interactions of this system of intercellular signaling with the effects of granulocyte colony-stimulating factor (G-CSF) on granulopoiesis in vivo. Elevation of extracellular adenosine in normal mice was induced by the joined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects of dipyridamole, AMP, and G-CSF, administered either alone or in combinations, were evaluated. The agents were injected to mice in a 4-day regimen, and the hematologic endpoints were determined 24 hours after the completion of the treatment. It was shown that the effects of G-CSF, ie, increases in peripheral blood neutrophils, granulocyte-macrophage progenitor cells (GM-CFC), and morphologically determined granulocytic cells in femoral marrow and a decrease in the marrow erythroid cells, can be enhanced by the combination of dipyridamole plus AMP administered 30 minutes before G-CSF. Furthermore, it was ascertained that the stimulatory action of dipyridamole plus AMP was expressed particularly at lower doses of G-CSF (1.5, 3, and 4.5 micrograms/d). At higher doses of G-CSF (6 and 9 micrograms/d), the interactions were no more evident. When combining dipyridamole, AMP, and 3 micrograms of G-CSF, peripheral neutrophils increased approximately 3.9- to 4.5-fold compared with an approximate 2.2-fold increase induced by G-CSF alone. The results indicate the possible therapeutic potential of combination therapy with G-CSF and drugs increasing extracellular adenosine.
Pospíŝil
M
M
Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
Hofer
M
M
Znojil
V
V
Vácha
J
J
Netíková
J
J
Holá
J
J
D000241:Adenosine / Q000096:biosynthesis*; D000249:Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology*; D004357:Drug Synergism; D005110:Extracellular Space / Q000378:metabolism*; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009504:Neutrophils / Q000166:cytology*; D011994:Recombinant Proteins / Q000494:pharmacology
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000249:Adenosine Monophosphate; D004176:Dipyridamole; D000241:Adenosine; D000069585:Filgrastim