Elevation of Extracellular Adenosine Induces Radioprotective Effects in Mice

Abstract

The radioprotective effectiveness of the elevation of extracellular adenosine induced in mice by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate, a soluble adenosine pro-drug, was evaluated. Based on survival studies, endogenous hemopoietic spleen colony formation, and the postirradiation behavior of bone marrow granulocyte-macrophage colony-forming cells (GM-CFC), it was demonstrated that the combined administration of dipyridamole and AMP protects mice when given either 15 or 60 min before irradiation. It could be deduced that the radioprotective action is induced by at least two independent mechanisms: (1) protection by hypoxia as a result of the effect of the treatment on the cardiovascular system, and (2) and enhanced regeneration of the hemopoietic stem cells due to either enhanced postirradiation repair or an increased proliferation of the hemopoietic stem cells. Both of these protective mechanisms, which are able to increase the regeneration of hemopoiesis, seemed to be effective in enhancing the survival of mice given single radiation exposures, with a dose reduction factor for the LD50/30 of 1.11. The protective efficiency of the mechanisms enhancing the postirradiation recovery of hemopoiesis was also evident in experiments evaluating the survival of mice subjected to fractionated irradiation and a repeated administration of the protective agents.

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

“…It stimulates the proliferation and differentiation of hematopoietic progenitors and also controls the functional activities of neutrophils and macrophages (Ikebuchi et al, 1988;Itoh et al, 1992). Our results are supported by those of Pospisil et al (1993Pospisil et al ( , 1995Pospisil et al ( , 1998, who showed that administration of adenosine monophosphate (AMP) combined with dypyridamole and G-CSF, prior to radiation, led to a radioprotective effect by the stimulation of haematopoiesis in the bone marrow and spleen of treated mice. The chemoprotective feature of the A3AR agonists is associated with other cytoprotective characteristics of these compounds.…”

Adenosine acts as a chemoprotective agent by stimulating G-CSF production: A role for A1 and A3 adenosine receptors

“…To the best of our knowledge, this is the first report that describes the presence of adenosine receptors on myeloid bone marrow progenitors, although such receptors have been defined on mature granulocytes, i.e., neutrophils (Cronstein, 1992). Pospisil et al (1993Pospisil et al ( , 1995Pospisil et al ( , 1998 showed that administration of adenosine monophosphate (AMP) combined with dipyridamole and G-CSF, prior to radiation, led to a radioprotective effect by the stimulation of hematopoiesis in the bone marrow and spleen of the treated mice. Jackson et al (1978) and Epstein and Preisler (1984) treated mice with the antimetabolite 6-thioguanine and demonstrated that adenosine exerted a protective effect on myeloid progenitor cells.…”

The pharmacological activation of adenosine A1 and A3 receptors does not modulate the long- or short-term repopulating ability of hematopoietic stem and multipotent progenitor cells in mice

“…Numerous studies have revealed the significant role of the nonselective activation of adenosine receptors in stimulating hematopoiesis [e.g., [10][11][12][13][14]. Discrimination between the hematopoiesismodulating effects of the activation of individual adenosine receptor types was made possible when selective adenosine receptor agonists became available.…”

“…In most of the above studies, the hematopoiesismodulating effects of the adenosine receptor agonists have been observed for both granulopoietic and erythroid lineages [10,11,13,15]. These results have been obtained from the levels in the peripheral blood or from the compartments of bone marrow precursor and committed progenitor cells.…”