Adenosine acts as a chemoprotective agent by stimulating G-CSF production: a role for A1 and A3 adenosine receptors.
Adenosine, a ubiquitous nucleoside, is released into the extracellular environment from metabolically active or stressed cells. It binds to cells through specific A1, A(2A), A(2B), and A3 G-protein-associated cell-surface receptors, thus acting as a signal-transduction molecule by regulating the levels of adenylyl cyclase and phospholipase C. In this study, we showed that adenosine stimulates the proliferation of murine bone marrow cells in vitro. Pharmacological studies, using antagonists to the adenosine receptors, revealed that this activity was mediated through the binding of adenosine to its A1 and A3 receptors. This result was further corroborated by showing that the two selective A1 and A3 receptor agonists, N-cyclopentyladenosine (CPA) and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-be ta-D-ribofuranuronamide (IB-MECA) respectively, induced bone marrow cell proliferation in a manner similar to adenosine. Adenosine's interaction with its A1 and A3 receptors induced G-CSF production, which led to its stimulatory effect on bone marrow cells. These results were confirmed in vivo when we demonstrated that low-dose adenosine (0.25 mg/kg) acted as a chemoprotective agent. When administered after chemotherapy, it restored the number of leukocytes and neutrophils to normal levels, compared with the decline in these parameters after chemotherapy alone. It is suggested that low-dose adenosine, already in clinical use, may also be applied as a chemoprotective agent.
Fishman
P
P
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Tel-Aviv University, Rabin Medical Center, Petach-Tikva, Israel. pnina@mor-research.com
Bar-Yehuda
S
S
Farbstein
T
T
Barer
F
F
Ohana
G
G
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000633:toxicity; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000494:pharmacology; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D014230:Triazoles; D014970:Xanthines; D016179:Granulocyte Colony-Stimulating Factor; C057837:3,7-dimethyl-1-propargylxanthine; D003520:Cyclophosphamide; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D013805:Theobromine