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.


METHODS
Experiments were performed under in vivo conditions using B10CBAF1 mice. The cycling status of hematopoietic progenitor cells (CFU-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.
Pospísil
M
M
Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
Hofer
M
M
Vacek
A
A
Netíková
J
J
Holá
J
J
Znojil
V
V
Weiterová
L
L
D000241:Adenosine / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000633:toxicity*; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002453:Cell Cycle / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004176:Dipyridamole / Q000494:pharmacology*; D004357:Drug Synergism; D005110:Extracellular Space / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology / Q000633:toxicity*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000502:physiology
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D018047:Receptors, Purinergic P1; D000249:Adenosine Monophosphate; D004176:Dipyridamole; D000241:Adenosine; D005472:Fluorouracil