Drugs elevating extracellular adenosine enhance cell cycling of hematopoietic progenitor cells as inferred from the cytotoxic effects of 5-fluorouracil
Objective. Our previous studies showed that the combined administration of drugs elevating extracellular adenosine, i.e., dipyridamole and adenosine monophosphate (AMP), enhanced hematopoiesis in normal mice and increased hematopoietic recovery in irradiated mice. In the present study, we have examined the possibility that these effects are due to the adenosine-induced cycling of the hematopoietic progenitor cells, Materials and Methods. Experiments were performed under in vivo conditions using B10CBAF1 mice. The cycling status of hematopoietic progenitor cells (CPU-S-day 10, CFC-GM, and BFU-E) was determined on the basis of their sensitivity to 5-fluorouracil (5-FU), a cycle-specific cytotoxic agent. Results. Pretreatment of mice with dipyridamole + AMP enhanced the cytotoxic effects of a single bolus of 5-FU at a dose of 3 mg per mouse. Sensitizing effects of drugs occurred after a delay of several hours and attained a maximum of about 40-60% reduction of the progenitor cells surviving after 5-FU alone. The period of maximum sensitization of CFU-S by the combination of dipyridamole + AMP was shifted to later time intervals as compared with the effects on CFC-GM and BFU-E, Pretreatment of mice with the drugs also aggravated the 5-FU-induced lethality. Reduction of survival was found in mice exposed to two cycles of 3 mg of 5-FU following the pretreatment with dipyridamole + AMP at a time period characterized by the highest fraction of CFU-S in the S phase. Conclusions. The results suggest that adenosine receptor signaling, induced by the administration of drugs elevating extracellular adenosine, enhances cycling of the hematopoietic progenitor cells. These effects might have pharmacological implications in the therapy of blood disorders. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science Inc.