The potential role of adenosine receptor signalling in the amplification of haemopoietic stem cells in vivo was investigated. Elevation of extracellular adenosine in mice was induced by the joint administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate, an adenosine prodrug. The response of haemopoietic stem cells to the drug treatment was measured by endogenous spleen colony-forming assay in sublethally gamma-irradiated animals. The combination of drugs was administered before irradiation either singly or repeatedly at 24 h intervals. The results demonstrated the possibility of enhancing the spleen colony formation by the drug treatment. The highest stimulatory effect on spleen colony counts and on the colony sizes occurred after 3-4 injections of the drugs. Higher spleen colony responses were observed under injection regimens terminated 3 h before irradiation, as compared to those terminated 24 h before the radiation exposure. The results are interpreted as an evidence of the expansion of the stem cell pool. A tolerance to this stimulatory action developed after more than 3 injections of the drugs.
Recent results of the authors have demonstrated that the elevation of extracellular adenosine induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), a soluble adenosine prodrug, mediates radioprotective effects in mice. Furthermore, it has been shown that this action is induced by at least two mechanisms: (1) protection by hypoxia as a result of the effects of treatment on the cardiovascular system (bradycardia, vasodilation), and (2) an enhanced regeneration of the radiation-perturbed hematopoiesis. Here, it was ascertained that the joint use of an optimal dose of noradrenaline given with dipyridamole and AMP combination eliminates the hypothermic and hypoxic effects of the treatment, but preserves the radioprotective action of dipyridamole and AMP combination in terms of hematopoietic recovery and partially also survival enhancing effects of the drugs in gamma-irradiated mice. These findings might be of importance for attempts to obtain available and tolerable radioprotective pharmacological prescriptions for clinical use.
We have recently demonstrated that the combined administration of dipyridamole and adenosine monophospate to mice induces radioprotective effects in terms of postirradiation haemopoietic recovery in animals irradiated with a single dose. The aim of the present experiments was to investigate the radioprotective ability of the drug combination under conditions of fractionated radiation treatment. It has been shown that administration of drugs either 15 or 60 min before each of the five daily 3-Gy doses of gamma-radiation enhances haemopoietic recovery and survival of mice exposed to an additional "top-up" dose of 3.5 Gy. Furthermore, it has been ascertained that the regimen using administration of the drugs 60 min prior to irradiation is more effective than administration of the drugs 15 min prior to irradiation. Due to the evidence that administration of the drugs 15 min prior to irradiation protects the organism mainly via mechanisms of systemic hypoxia while the pretreatment 60 min before irradiation avoids the role of hypoxia and mainly induces cell proliferation effects, our results suggest a more effective protective role of mechanisms stimulating haemopoiesis under conditions of fractionated radiation. The data may provide a basis for more rational use of radioprotection in fractionated radiation regimens.
Differences in lipid metabolism of tumor and normal tissues suggest a distinct response to available lipid compounds. In this study, the in vitro effects of five types of commercial parenteral lipid emulsions were investigated on human cell lines derived from normal fetal colon (FHC) or colon adenocarcinoma (HT-29). Changes of the cellular lipid fatty acid content, cell oxidative response, and the cell growth and death rates were evaluated after 48 h. No effects of any type of emulsions were detected on cell proliferation and viability. Compared to the controls, supplementation with lipid emulsions resulted in a multiple increase of linoleic and linolenic acids in total cell lipids, but the content of arachidonic, eicosapentaenoic, and docosahexaenoic acids decreased particularly in HT-29 cells. The concentration of emulsions which did not affected HT-29 cells increased the percentage of floating and subG0/G1 FHC cells probably due to their higher reactive oxygen species production and lipid peroxidation. Co-treatment of cells with antioxidant Trolox reduced the observed effects. Our results imply that lipid emulsions can differently affect the response of colon cells of distinct origin.