Meloxicam, a selective inhibitor of cyclooxygenase 2, was tested to determine its ability to modulate hematopoiesis and to influence survival of mid-lethally gamma-irradiated mice. A single dose of meloxicam (20 mg/kg) administered to mice intraperitoneally 1 h before irradiation was shown to enhance serum levels of granulocyte colony-stimulating factor (G-CSF) during the first 24 h after irradiation, to elevate numbers of granulocytic precursor cells in bone marrow and granulocyte counts in peripheral blood on day 10 after irradiation, and to increase 30-day survival of these mice. The results provide new evidence for the protective ability of meloxicam administration to mice irradiated with mid-lethal doses and contribute to the understanding of the mechanisms of this meloxicam action by drawing attention to the possible role of increased endogenous G-CSF production.

We tested capabilities of drugs elevating extracellular adenosine and of granulocyte colony-stimulating factor (G-CSF) given alone or in combination to modulate regeneration from severe myelosuppression resulting from combined exposure of mice to ionizing radiation and carboplatin. Elevation of extracellular adenosine was induced by joint administration of dipyridamole (DP), a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), serving as an adenosine prodrug. DP+AMP, G-CSF or all these drugs in combination were administered in a 4-d treatment regimen starting on day 3 after induction of myelosuppression. Comparable enhancements of haematopoietic regeneration due to elevation of extracellular adenosine or to action of G-CSF were demonstrated as shown by elevated numbers of haematopoietic progenitor cells for granulocytes/macrophages (GM-CFC) and erythrocytes (BFU-E) in the bone marrow and spleen in early time intervals after termination of the drug treatment, i.e. on days 7 and 10 after induction of myelosuppression. Coadministration of all the drugs further potentiated the restoration of progenitor cell pools in the haematopoietic organs. The effects of the drug treatments on progenitor cells were reflected in the peripheral blood in later time intervals of days 15 and 20 after induction of myelosuppression, especially as significantly elevated numbers of granulocytes and less pronounced elevation of lymphocytes and erythrocytes. The results substantiate the potential of drugs elevating extracellular adenosine for clinical utilization in myelosuppressive states, e.g. those accompanying oncological radio- and chemotherapy.

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.