Influence of the joint treatment with granulocyte colony-stimulating factor and drugs elevating extracellular adenosine on erythropoietic recovery following 5-fluorouracil-induced haematotoxicity in mice

The presented data address the problem of pleiotropic effects of granulocyt e colony-stimulating factor (G-CSF) and suggest the ability of drugs increa sing the level of extracellular adenosine to activate erythropoiesis when g iven jointly with G-CSF. To demonstrate these interactions, the effects of the drugs on the recovery from erythropoietic damage induced in mice by a s ingle dose of 5-fluorouracil (5-FU) were investigated. Elevation of extrace llular adenosine and thus activation of adenosine receptors was induced by joint administration of dipyridamole (DP), a drug inhibiting the cellular u ptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug . The drugs were injected in a 4-d treatment regimen starting 2 h after 5-F U injection. Both DP + AMP and G-CSF alone induced only weak effects. Howev er, the combination of the three drugs produced significant elevation of er ythrocytes in the peripheral blood which pertained in the post-treatment pe riod. Stimulation of proliferation of erythroid progenitor cells (BFU-E) in femoral bone marrow and increased levels of reticulocytes in the periphera l blood were observed in the course of the 4-d treatment regimen. In additi on, significantly decreased mean cell haemoglobin accompanying the elevated numbers of erythrocytes in the combination-treated mice was found. This ef fect could be interpreted as the result of a sublethal 5-FU-induced damage to erythroid progenitor and precursor cells forced to proliferate intensive ly by the combination therapy. The observed additivity and synergism of G-C SF with elevated extracellular adenosine in terms of erythropoiesis is an i nteresting finding with potential implications in clinical practice.