Drugs elevating extracellular adenosine promote regeneration of haematopoietic progenitor cells in severely myelosuppressed mice: their comparison and joint effects with the granulocyte colony-stimulating factor.
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.
Hofer
Michal
M
Institute of Biophysics, Institute of Sciences of the Czech Republic, Královopolská 135, CZ-612 Brno, Czech Republic. hofer@ibp.cz
Pospísil
Milan
M
Znojil
Vladimír
V
Vacek
Antonín
A
Weiterova
Lenka
L
Holá
Jirina
J
Vácha
Jirí
J
D000241:Adenosine / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001772:Blood Cell Count; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D016190:Carboplatin / Q000633:toxicity; D004176:Dipyridamole / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D015672:Erythroid Precursor Cells / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D008214:Lymphocytes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D010198:Pancytopenia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D014916:Whole-Body Irradiation / Q000009:adverse effects
D011355:Prodrugs; D016179:Granulocyte Colony-Stimulating Factor; D000249:Adenosine Monophosphate; D004176:Dipyridamole; D016190:Carboplatin; D000241:Adenosine