Adenosine has been observed to suppress the growth of MOLT-4 human leukemia cells in vitro. Changes in the cell cycle, especially increased percentage of cells in S phase, prolonged generation time, and induction of apoptosis at higher adenosine concentrations have been found to be responsible for the growth suppression. Dipyridamole, a drug inhibiting the cellular uptake of adenosine, reversed partially but significantly the adenosine-induced growth suppression. It follows from these results that the action of adenosine on the MOLT-4 cells comprises its cellular uptake and intracellular operation. These findings present new data on anticancer efficacy of adenosine.

• MeSH
• adenosin antagonisté a inhibitory   metabolismus   farmakologie   MeSH
• apoptóza MeSH
• biologický transport účinky léků   MeSH
• dipyridamol farmakologie   MeSH
• inhibitory fosfodiesteras farmakologie   MeSH
• leukemie T-buněčná patologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky antagonisté a inhibitory   metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• dipyridamol MeSH
• inhibitory fosfodiesteras MeSH
• protinádorové látky MeSH

Our previous studies have shown that the combined administration of drugs elevating extracellular adenosine, i.e. dipyridamole (DP) and adenosine monophosphate (AMP), enhances murine hematopoiesis and potentiates the action of granulocyte colony-stimulating factor (G-CSF). In this study, colony-stimulating activity (CSA) of blood serum of mice treated with DP+AMP, G-CSF or all these drugs in combination, i.e. the ability of the sera to stimulate the growth of GM-CFC colonies, was assayed in vitro. Furthermore, the concentration of GM-CSF and IL-6 in the sera was determined. Administration of DP+AMP was found to enhance significantly serum CSA at all time intervals of serum sampling including 24 h after the last injection of the tested drugs. Additive effects of DP+AMP and G-CSF on serum CSA were noted at early intervals after administration of the drugs. Furthermore, IL-6 levels were significantly elevated in the sera of mice which were administered DP+AMP either alone or in combination with G-CSF. Our results show that the effects of DP+AMP are indirect, mediated through the induction of some cytokine(s) and/or growth factor(s) and that extracellular adenosine can act in cooperation with G-CSF. These findings contribute to the further elucidation of the role of adenosine in hematopoiesis.

• MeSH
• adenosin metabolismus   MeSH
• adenosinmonofosfát metabolismus   farmakologie   MeSH
• analýza kolonii tvořících jednotek MeSH
• časové faktory MeSH
• dipyridamol farmakologie   MeSH
• faktor stimulující granulocyto-makrofágové kolonie krev   metabolismus   MeSH
• faktor stimulující kolonie granulocytů metabolismus   farmakologie   MeSH
• hematopoetické kmenové buňky účinky léků   metabolismus   MeSH
• hematopoéza účinky léků   MeSH
• interleukin-6 krev   metabolismus   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• adenosinmonofosfát MeSH
• dipyridamol MeSH
• faktor stimulující granulocyto-makrofágové kolonie MeSH
• faktor stimulující kolonie granulocytů MeSH
• interleukin-6 MeSH

Polymorphonuclear neutrophils (PMN) are thought to play a role in reperfusion injury and ischemia. These effects are partly mediated by toxic oxygen species (superoxide anion, hydrogen peroxide and hydroxyl radical) acting at the level of the endothelium. It was demonstrated recently that the superoxide anion reacts with nitric oxide (NO) and that interaction leads to the generation of highly toxic peroxynitrite. Several drugs were tested so far in order to affect PMN function. It was demonstrated that dipyridamole (2,6-bis-diethanolamino-4,8-dipiperidinopyrimido-(5,4-d)-pyrimidine) can influence neutrophil function by inhibiting adenosine uptake. However, this action can not fully explain all of the observed effects of dipyridamole action on PMN metabolism. The aim of our study was to evaluate the influence of dipyridamole on nitric oxide production by activated polymorphonuclear neutrophils. Incubation of PMNs with hydroxylamine (HA) and phorbol myristate acetate (PMA) generated nitrite (36.4+/-4.2 nmol/h 2x10(6) PMN), dipyridamole at 100 micromol/l, 50 micromol/l and 10 micromol/l caused a considerable drop in nitrite production (11.8+/-1.8, 19.7+/-2.7 and 27.4+/-3.2 nmol/h, respectively). Neither adenosine nor the adenosine analogue could mimic the dipyridamole effect. Moreover theophylline, an adenosine inhibitor could not reverse the dipirydamole action on PMN metabolism. We also found that dipyridamole inhibited hydrogen peroxide release from neutrophils. Catalase that scavenges hydrogen peroxide also largely abolished nitric oxide release from PMN. It is evident that dipyridamole inhibits hydroxylamine-augmented nitric oxide production by activated polymorphonuclear neutrophils through an adenosine-independent mechanism.

• MeSH
• adenosin metabolismus   MeSH
• aktivace neutrofilů účinky léků   MeSH
• dipyridamol farmakologie   MeSH
• fixní kombinace léků MeSH
• hydroxylamin farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• neutrofily účinky léků   metabolismus   MeSH
• oxid dusnatý biosyntéza   MeSH
• peroxid vodíku metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenosin MeSH
• dipyridamol MeSH
• fixní kombinace léků MeSH
• hydroxylamin MeSH
• oxid dusnatý MeSH
• peroxid vodíku MeSH

It has been observed that adenosine suppresses the growth of G:5:113 murine fibrosarcoma cells in vitro with EC50 of 178 mM. Changes in the cell cycle including decreased percentage of cells in S-phase, increased portion of cells in G0/G1-phase, as well as prolonged generation time were found to be responsible for the growth suppression. Dipyridamole, a drug inhibiting the cellular uptake of adenosine, enhanced the growth suppression induced with adenosine in concentrations of 100 and 200 microM. It follows from these results that the action of adenosine on the G:5:113 cells is extracellular, mediated by adenosine receptors. Elevation of extracellular adenosine might serve potentially as an anticancer therapeutic agent.

• MeSH
• adenosin farmakologie   MeSH
• buněčné dělení účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• dipyridamol farmakologie   MeSH
• fibrosarkom patologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• dipyridamol MeSH

We tested the capabilities of drugs elevating extracellular adenosine and of granulocyte colony-stimulating factor (G-CSF), given alone or in combination, to mobilize haematopoietic progenitor cells for granulocytes and macrophages (GM-CFC) and granulocytes into peripheral blood. 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 either singly or repeatedly in a 4-d treatment regimen. Elevation of extracellular adenosine was found to mobilize significantly both GM-CFC and granulocytes after both single and repeated administration of DP + AMP. These results show that the elevation of extracellular adenosine presents a potent mechanism for mobilization of GM-CFC and granulocytes into the blood. When the combination of DP + AMP + G-CSF was given under the 4-d regimen, the mobilizing effects of its administration were additive when compared with those of DP + AMP alone or G-CSF alone. The observed ability of the drugs elevating extracellular adenosine to enhance the mobilizing action of G-CSF points out possible practical utilization of the findings presented here. This conclusion is further supported by the results of an additional experiment which indicate that blocking of haemodynamic side effects of drugs elevating extracellular adenosine by noradrenaline does not suppress their mobilizing effects.

• MeSH
• adenosin metabolismus   MeSH
• adenosinmonofosfát farmakologie   MeSH
• dipyridamol farmakologie   MeSH
• extracelulární prostor metabolismus   MeSH
• faktor stimulující kolonie granulocytů farmakologie   MeSH
• granulocyty cytologie   MeSH
• hematopoetické kmenové buňky cytologie   MeSH
• makrofágy cytologie   MeSH
• myši inbrední C57BL MeSH
• myši inbrední CBA MeSH
• myši MeSH
• počet buněk MeSH
• pohyb buněk MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• adenosinmonofosfát MeSH
• dipyridamol MeSH
• faktor stimulující kolonie granulocytů MeSH

Up to 20% to 30% of patients with angina and abnormal stress test have normal coronary arteries at angiography or syndrome X (Sy X). We tested whether body surface potential mapping (BSPM) with intravenous dipyridamole could differentiate patients with Sy X from patients with coronary artery disease (CAD). We compared the effects of intravenous dipyridamole (0.28 mg/kg over 4 min) on BSPM in 17 healthy volunteers (controls) and in 2 groups of patients with angina and abnormal ergometric tests who were referred for angiography: 27 patients with obstructive disease (> or =70% diameter stenosis) in the CAD group, and 17 patients with Sy X. Control subjects were easily differentiated from patients with CAD or Sy X by markedly smaller baseline BSPM DeltaST-T < or = LSD departure areas (P <.001), but the Sy X and CAD groups had similar ST-T departure areas. The average potential integral difference after dipyridamole (APID) differentiated Sy X and CAD patients: the mean APID increased in patients with Sy X and trended negative in the CAD group. The APID(20%-40%) (integrated over 20% to 40% of the ST-T interval) mean value was 0.59 +/- 0.67 microVs in the Sy X group and -0.18 +/- 0.59 microVs in the CAD group (P <.01). At a threshold APID(20%-40%) > 0.17 microVs, the sensitivity and specificity for Sy X was 71% and 78%, respectively; the area under the receiver operating characteristic curve was 0.79 (95% CI 0.64, 0.93). Dipyridamole BSPM is a promising noninvasive diagnostic modality to differentiate patients with Sy X from those with CAD.

• MeSH
• diferenciální diagnóza MeSH
• dipyridamol aplikace a dávkování   farmakologie   MeSH
• injekce intravenózní MeSH
• koronární angiografie MeSH
• koronární nemoc diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mapování potenciálů tělesného povrchu účinky léků   MeSH
• mikrovaskulární angina pectoris diagnóza   MeSH
• senzitivita a specificita MeSH
• zátěžový test MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipyridamol MeSH

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.

• MeSH
• adenosin metabolismus   MeSH
• adenosinmonofosfát farmakologie   terapeutické užití   MeSH
• celotělové ozáření škodlivé účinky   MeSH
• dipyridamol farmakologie   terapeutické užití   MeSH
• erytroidní prekurzorové buňky patologie   MeSH
• extracelulární prostor metabolismus   MeSH
• faktor stimulující kolonie granulocytů farmakologie   terapeutické užití   MeSH
• hematopoetické kmenové buňky patologie   MeSH
• karboplatina toxicita   MeSH
• kostní dřeň účinky léků   patologie   účinky záření   MeSH
• krevní obraz MeSH
• lymfocyty patologie   MeSH
• makrofágy patologie   MeSH
• myši inbrední C57BL MeSH
• myši inbrední CBA MeSH
• myši MeSH
• pancytopenie farmakoterapie   etiologie   metabolismus   patologie   MeSH
• preklinické hodnocení léčiv MeSH
• prekurzory léčiv farmakologie   terapeutické užití   MeSH
• synergismus léků MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• adenosin MeSH
• adenosinmonofosfát MeSH
• dipyridamol MeSH
• faktor stimulující kolonie granulocytů MeSH
• karboplatina MeSH
• prekurzory léčiv MeSH

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. MATERIALS AND 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.

• MeSH
• adenosin metabolismus   MeSH
• adenosinmonofosfát farmakologie   MeSH
• analýza kolonii tvořících jednotek MeSH
• buněčný cyklus účinky léků   MeSH
• dipyridamol farmakologie   MeSH
• extracelulární prostor metabolismus   MeSH
• fluoruracil farmakologie   toxicita   MeSH
• hematopoetické kmenové buňky cytologie   účinky léků   metabolismus   MeSH
• myši MeSH
• nemoci kostní dřeně chemicky indukované   MeSH
• prekurzory léčiv farmakologie   MeSH
• protinádorové antimetabolity farmakologie   toxicita   MeSH
• purinergní receptory P1 účinky léků   fyziologie   MeSH
• synergismus léků MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• adenosinmonofosfát MeSH
• dipyridamol MeSH
• fluoruracil MeSH
• prekurzory léčiv MeSH
• protinádorové antimetabolity MeSH
• purinergní receptory P1 MeSH

The presented data address the problem of pleiotropic effects of granulocyte colony-stimulating factor (G-CSF) and suggest the ability of drugs increasing the level of extracellular adenosine to activate erythropoiesis when given jointly with G-CSF. To demonstrate these interactions, the effects of the drugs on the recovery from erythropoietic damage induced in mice by a single dose of 5-fluorouracil (5-FU) were investigated. Elevation of extracellular adenosine and thus activation of adenosine receptors was induced by joint administration of dipyridamole (DP), a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The drugs were injected in a 4-d treatment regimen starting 2 h after 5-FU injection. Both DP+AMP and G-CSF alone induced only weak effects. However, the combination of the three drugs produced significant elevation of erythrocytes in the peripheral blood which pertained in the posttreatment period. Stimulation of proliferation of erythroid progenitor cells (BFU-E) in femoral bone marrow and increased levels of reticulocytes in the peripheral blood were observed in the course of the 4-d treatment regimen. In addition, significantly decreased mean cell haemoglobin accompanying the elevated numbers of erythrocytes in the combination-treated mice was found. This effect could be interpreted as the result of a sublethal 5-FU-induced damage to erythroid progenitor and precursor cells forced to proliferate intensively by the combination therapy. The observed additivity and synergism of G-CSF with elevated extracellular adenosine in terms of erythropoiesis is an interesting finding with potential implications in clinical practice.

• MeSH
• adenosin metabolismus   farmakologie   MeSH
• adenosinmonofosfát farmakologie   terapeutické užití   MeSH
• antimetabolity toxicita   MeSH
• časové faktory MeSH
• dipyridamol farmakologie   terapeutické užití   MeSH
• erytrocyty cytologie   účinky léků   MeSH
• erytroidní prekurzorové buňky cytologie   účinky léků   MeSH
• erytropoéza účinky léků   MeSH
• faktor stimulující kolonie granulocytů farmakologie   terapeutické užití   MeSH
• fluoruracil toxicita   MeSH
• hemoglobiny účinky léků   metabolismus   MeSH
• inhibitory fosfodiesteras farmakologie   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• myši inbrední C57BL MeSH
• myši inbrední CBA MeSH
• myši MeSH
• počet erytrocytů MeSH
• retikulocyty cytologie   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• adenosinmonofosfát MeSH
• antimetabolity MeSH
• dipyridamol MeSH
• faktor stimulující kolonie granulocytů MeSH
• fluoruracil MeSH
• hemoglobiny MeSH
• inhibitory fosfodiesteras MeSH

The frequency of micronucleated polychromatic erythrocytes (PCEs) in mouse bone marrow was assessed after administration of dipyridamole and/or adenosine monophosphate (AMP) to nonirradiated mice or to mice irradiated 15 min later with a sublethal dose of 6.5 Gy gamma rays. In nonirradiated mice, the administration of the drugs increased the frequency of micronucleated PCEs significantly (by 108%). In contrast, in irradiated mice, the number of radiation-induced micronucleated PCEs was significantly decreased if the mice had been pretreated with dipyridamole or AMP alone (by 24% after administration of each of the compounds) and in particular after administration of the drugs in combination (by 36%).

• MeSH
• adenosinmonofosfát farmakologie   MeSH
• buňky kostní dřeně účinky léků   účinky záření   ultrastruktura   MeSH
• chromozomální aberace MeSH
• dipyridamol farmakologie   MeSH
• erytrocyty účinky léků   účinky záření   ultrastruktura   MeSH
• fixní kombinace léků MeSH
• inbrední kmeny myší MeSH
• inhibitory fosfodiesteras farmakologie   MeSH
• mikrojaderné testy MeSH
• myši MeSH
• poškození DNA MeSH
• radioprotektivní látky farmakologie   MeSH
• záření gama MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosinmonofosfát MeSH
• dipyridamol MeSH
• fixní kombinace léků MeSH
• inhibitory fosfodiesteras MeSH
• radioprotektivní látky MeSH