GRANULOCYTE-COLONY-STIMULATING FACTOR AND DRUGS ELEVATING EXTRACELLULAR ADENOSINE SYNERGIZE TO ENHANCE HEMATOPOIETIC RECONSTITUTION IN IRRADIATED MICE

The activation of adenosine receptors has recently been demonstrated t o stimulate haematopoiesis. In the present study, we investigated the ability of drugs elevating extracellular adenosine to influence curati ve effects of granulocyte colony-stimulating factor (G-CSF) in mice ex posed to a sublethal dose of 4 Gy of Co-60 radiation. Elevation of ext racellular adenosine in mice was induced by the combined administratio n of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects of dipyridamole plus AMP, and G-CSF, administered either alone or in c ombination, were evaluated. The drugs were injected to mice in a 4-d t reatment regimen starting on d3 after irradiation and the haematopoiet ic response was evaluated on d 7, 10, 14, 18 and 24 after irradiation. While the effects of G-CSF on the late maturation stages of blood cel ls, appearing shortly after the completion of the treatment, were not influenced by dipyridamole plus AMP, positive effects of the combinati on therapy occurred in the post-irradiation recovery phase which is de pendent on the repopulation of haematopoietic stem cells. This was ind icated by the significant elevation of counts of granulocyte-macrophag e progenitor cells (GM-CFC) and granulocytic cells in the bone marrow (d 14), of GM-CFC (d 14), granulocytic and erythroid cells (d 14 and 1 8) in the spleen, and of neutrophils (d 18), monocytes (d 14 and 18) a nd platelets (d 18) in the peripheral blood. These effects suggest tha t the repopulation potential of the combination therapy lies in a comm on multilineage cell population. The results of this study implicate t he promising possibility to enhance the curative effects of G-CSF unde r conditions of myelosuppressive states induced by radiation exposure.