Michal Hofer - Academia.edu (original) (raw)

Papers by Michal Hofer

Molecules, 2011

The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopo... more The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopoietic functions. The studies carried out utilized either non-selective activation of adenosine receptors induced by elevation of extracellular adenosine or by administration of synthetic adenosine analogs having various proportions of selectivity for a particular receptor. Numerous studies have described stimulatory effects of non-selective activation of adenosine receptors, manifested as enhancement of proliferation of cells at various levels of the hematopoietic hierarchy. Subsequent experimental approaches, considering the hematopoiesis-modulating action of adenosine receptor agonists with a high level of selectivity to individual adenosine receptor subtypes, have revealed differential effects of various adenosine analogs. Whereas selective activation of A 1 receptors has resulted in suppression of proliferation of hematopoietic progenitor and precursor cells, that of A 3 receptors has led to stimulated cell proliferation in these cell compartments. Thus, A 1 and A 3 receptors have been found to play a homeostatic role in suppressed and regenerating hematopoiesis. Selective activation of adenosine A 3 receptors has been found to act curatively under conditions of drug-and radiation-induced myelosuppression. The findings in these and further research areas will be summarized and mechanisms of hematopoiesis-modulating action of adenosine receptor agonists will be discussed.

Two adenosine receptor agonists, N 6-(3-iodobenzyl)adenosine- 59-N-methyluronamide (IB-MECA) and ... more Two adenosine receptor agonists, N 6-(3-iodobenzyl)adenosine- 59-N-methyluronamide (IB-MECA) and N 6-cyclopentyladenosine (CPA), which selectively activate adenosine A3 and A1 receptors, respectively, were tested for their ability to influence prolifer- ation of granulocytic and erythroid cells in femoral bone marrow of mice using morphological criteria. Agonists were given intraperitoneally to mice in repeated isomolar doses of 200 nmol/kg. Three variants of

Neoplasma

Nordihydroguaiaretic acid (NDGA) and esculetin, both nonspecific inhibitors of lipoxygenases (LOX... more Nordihydroguaiaretic acid (NDGA) and esculetin, both nonspecific inhibitors of lipoxygenases (LOX), were found to suppress expressively the in vitro proliferation of fibrosarcoma cells G5:113 in concentrations ranging from 10 to 50 microM. Subsequent flow-cytometric analysis of the cell cycle showed that both these drugs significantly decreased the percentage proportion of cells in the G0/G1-phase and simultaneously increased significantly this proportion in the S-phase. No apoptosis was detected in the whole range of concentrations studied, from 2.5 to 50 mM. On the contrary, in experiments in vivo, neither NDGA nor esculetin had any curative effect if they were repeatedly injected intraperitoneally (i.p.) into mice bearing tumors growing from subcutaneously (s.c.) transplanted G5:113 cells. Pretreatment of the fibrosarcoma cells with NDGA or esculetin in vitro preceding their s.c. transplantation into mice did not result in suppression of the tumor growth, either. Finally, if G5:113 cells were injected intravenously and the mice were subsequently treated repeatedly with i.p. injections of NDGA, decreased survival and increased number of surface lung metastases were observed in the NDGA-treated group. Thus the suppressive action of inhibitors of LOX on the growth of fibrosarcoma cells in vitro was not reflected in their anti-tumor effects in vivo.

Physiological research / Academia Scientiarum Bohemoslovaca

The present studies investigated changes in expression of mRNA for adenosine A 1 , A 2a , A 2b , ... more The present studies investigated changes in expression of mRNA for adenosine A 1 , A 2a , A 2b , and A 3 receptors in samples of HL-60 promyelocytic cells differing in the actual presence of cells in various phases of the cell cycle induced by the double thymidine block method. Realtime PCR technique was used for obtaining data on mRNA expression. Statistical analysis of the data revealed that the mRNA expression of adenosine A 1 , A 2a , and A 3 receptors is dependent on the cell cycle phase. G 0 /G 1 and G 2 /M phases were characterized by a higher mRNA expression of adenosine A 1 receptors and a lower one of adenosine A 2a and A 3 receptors whereas the opposite was true for the S phase. Interestingly, expression of mRNA of the adenosine A 2b receptors was independent on the cell cycle phase. The results indicate the plasticity of mRNA expression of adenosine receptors in the investigated promyelocytic cells and its interaction with physiological mechanisms of the cell cycle.

Central European Journal of Biology, 2006

Inhibitors of prostaglandin production, designated as classical non-steroidal antiinflammatory dr... more Inhibitors of prostaglandin production, designated as classical non-steroidal antiinflammatory drugs (NSAIDs) and acting on the base of non-selective inhibition of cyclooxygenases, have been found in numerous studies to potentiate recovery of perturbed haematopoiesis by removing the negative feedback control mediated by prostaglandins. However, classical NSAIDs show pronounced undesirable gastrointestinal side effects, which limits the possibility of their utilization for various pathophysiological states including myelosuppression. Specific cyclooxygenase-2 (COX-2) inhibitors, targeted at selective inhibition of this inducible cyclooxygenase isoform and having much better gastrointestinal side effect profile, have been found in recent studies to retain the haematopoiesisstimulating effects of classical NSAIDs. These results suggest that the indication spectrum of selective COX-2 inhibitors may be extended to the indication of myelosuppression of various etiology. Combining the anti-tumour and haematopoiesis-stimulating activities in a single COX-2 inhibitor may have a positive clinical impact.

Purinergic signalling, 2015

Adenosine A3 receptor knockout (A3AR KO) mice and their wild-type (WT) counterparts were compared... more Adenosine A3 receptor knockout (A3AR KO) mice and their wild-type (WT) counterparts were compared from the point of view of their abilities to survive exposures to lethal doses of γ-radiation belonging to the range of radiation doses inducing the bone marrow acute radiation syndrome. Parameters of cumulative 30-day survival (experiment using a midlethal radiation dose) or cumulative 11-day survival (experiment using an absolutely lethal radiation dose), and of mean survival time were evaluated. The values of A3AR KO mice always reflected their higher survival in comparison with WT ones, the P values being above the limit for statistical significance after the midlethal radiation dose and standing for statistical significance after the absolutely lethal radiation dose. This finding was considered surprising, taking into account the previously obtained findings on defects in numbers and functional properties of peripheral blood cells in A3AR KO mice. Therefore, previous hematological ...

Physiological research / Academia Scientiarum Bohemoslovaca, 2010

Expression of mRNA for adenosine receptor subtypes A(1), A(2a), A(2b), and A(3) in normal and lip... more Expression of mRNA for adenosine receptor subtypes A(1), A(2a), A(2b), and A(3) in normal and lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages has been investigated using the method of quantitative real-time polymerase chain reaction. The results have shown a very low, unquantifiable expression of adenosine A(1) receptor mRNA in both normal and LPS-activated macrophages. The other three adenosine receptor mRNAs have been found to be expressed at various but always quantifiable levels. Activation of the macrophages by LPS induced upregulation of the expression of adenosine receptor A(2a) and A(2b) mRNA, whereas the expression of adenosine receptor A(3) mRNA was downregulated. Unstimulated macrophages exhibited a high expression of the A(2b) adenosine receptor mRNA. The findings are discussed from the point of view of the antiinflammatory and hematopoiesis-stimulating roles of the adenosine receptor signaling.

International journal of immunopharmacology, 2000

It has been demonstrated that the synthetic immunostimulatory compound, adamantylamide dipeptide ... more It has been demonstrated that the synthetic immunostimulatory compound, adamantylamide dipeptide (AdDP) produces hematopoiesis-stimulating effects in mice exposed to sublethal doses of ionizing radiation and increases survival in experimental animals irradiated with a lethal dose. These findings might suggest contingent extension of clinical indications for the administration of AdDP for the conditions of hematopoietic suppression, especially in oncology.

International journal of immunopharmacology

Protection from undesirable effects of radiotherapy or chemotherapy, primarily from myelosuppress... more Protection from undesirable effects of radiotherapy or chemotherapy, primarily from myelosuppression, remains still a crucial problem to be studied. Attention has been therefore paid to various immunomodulatory agents that through the monocyte/macrophage system induced production of cytokines, which can induce and operate restoration of haemopoiesis and thus act radioprotectively. Some synthetic analogues of MDP free of undesirable side-effects, were synthesized in the Czech Republic. Lipophilic beta-D-GlcNstearoyl-(1- > 4)-norMurNAc-L-Abu-D-isoGln (DDD-St) was designed to be easily entrapped into liposomes and this liposomal DDD-St protected efficiently mice against irradiation, when administered i.p., i.v. or s.c. 24 h prior to lethal irradiation (survival rate in the range of 30-80% compared with 0% in control). Especially the subcutaneous application of liposomal DDD-St was very efficient. The parameters characteristic of recovery of haemopoiesis in bone marrow on day 10 afte...

International journal of immunopharmacology

Glucan, a beta-1,3-linked polyglucose derived from the yeast Saccharomyces cerevisiae, is a broad... more Glucan, a beta-1,3-linked polyglucose derived from the yeast Saccharomyces cerevisiae, is a broad spectrum enhancer of host defense mechanisms stimulating humoral and cell-mediated immunity. On the basis of these features, glucan has been tested by the authors' research group in experiments on gamma-irradiated mice. Two glucan forms, particulate and soluble, have been studied. Attention has been focused on various application regimens in relation to the time of irradiation (pre- or postirradiation application), the possibilities of using glucan in various radiation regimens (single or repeated irradiation), combined pharmacological therapy (joint administration of glucan with cystamine or inhibitors of prostaglandin synthesis), and on the negative side effects of therapy with glucan. Some studies included also experiments on unirradiated mice. The results have demonstrated the ability of glucan to influence positively the course of the acute radiation disease. Stimulation of hem...

Biomedicine & Pharmacotherapy, 2007

The present study was performed to define the optimum conditions of the stimulatory action of the... more The present study was performed to define the optimum conditions of the stimulatory action of the adenosine A3 receptor agonist, N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA), on bone marrow hematopoiesis in mice. Effects of 2-day treatment with IB-MECA given at single doses of 200nmol/kg twice daily were investigated in normal mice and in mice whose femoral bone marrow cells were either depleted or regenerating

International Journal of Immunopharmacology, 1997

The influence of dialyzable extract from human leukocytes (DLE) on the in vitro growth of the gra... more The influence of dialyzable extract from human leukocytes (DLE) on the in vitro growth of the granulocyte-macrophage colony-forming cell (GM-CFC) colonies from progenitors of mouse bone marrow cells was studied. DLE alone did not induce the colony growth but it modulated the number of colonies if administered together with a colony-stimulating factor (CSF).

International Journal of Immunopharmacology, 2000

Dialyzed leukocyte extract (DLE) (Immodin SEVAC, Czech Republic) was shown to enhance the recover... more Dialyzed leukocyte extract (DLE) (Immodin SEVAC, Czech Republic) was shown to enhance the recovery of the pools of hemopoietic stem cells (CFUs) and of granulocyte±macrophage hemopoietic progenitor cells (GM-CFC) in the bone marrow in vivo, as well as to increase the numbers of leukocytes and thrombocytes in the peripheral blood of mice exposed to a sublethal dose of gamma-rays, with an ensuing increase in the numbers of mice surviving the lethal radiation dose. In experiments performed in vitro, DLE or sera of mice administered with DLE were added to cultures of intact mouse bone marrow cells containing suboptimal concentrations of hemopoietic stimulatory cytokines, namely recombinant mouse interleukin-3 (rmIL-3) or recombinant mouse granulocyte±macrophage colony-stimulating factor (rmGM-CSF); under these experimental conditions, both DLE and sera of mice administered DLE were found to increase the counts of GM-CFC colonies in the cultures. It can be hypothesized on the basis of the ®ndings obtained in vitro that the described co-stimulating activity (CoSA) of DLE may play a role also under in vivo conditions; the enhancement of the recovery of hemopoiesis suppressed by ionizing radiation may be due to a co-operation of the stimulatory eects of DLE with the action of cytokines endogenously produced in irradiated tissues. 7

International Journal of Immunopharmacology, 1995

The hemopoiesis-enhancing ability of a soluble glucan derivative, i.e. carboxymethylglucan (CMG),... more The hemopoiesis-enhancing ability of a soluble glucan derivative, i.e. carboxymethylglucan (CMG), was investigated in gamma-irradiated mice. Attention was focused on the usefulness of its single or repeated postirradiation administration. CMG was administered i.p. at (a) single dose of 6 mg 2 h postirradiation, (b) four 6 mg doses in the first 4 days postirradiation, (c) four 1.5 mg doses at the same time intervals. Indices of granulopoiesis and inflammatory side effects (liver weight increase and hepatic granulomas) were investigated in mice irradiated with a sublethal dose of 7 Gy. All three CMG-treated groups of mice were found to exhibit enhanced hemopoietic recovery in comparison with the controls. Although the mice repeatedly given the 6 mg CMG doses showed the most rapid recoveries of all the evaluated parameters of granulopoiesis, the most pronounced hepatic side effects were found in these mice, too. When survival of mice was recorded in lethally (9 Gy) irradiated animals, the best protective response were obtained following the repeated administration of the 1.5 mg CMG dose, the survival by day 30 in this group being significantly higher not only in comparison with the controls but also with the mice repeatedly given the 6 mg dose of CMG. The results suggest that the postirradiation CMG administration can be useful for enhancing radiation suppressed hemopoiesis. However, repeated larger CMG doses may produce side effects which compromise the overall survival of irradiated mice.

Cancer Investigation, 2002

Strahlentherapie und Onkologie, 2001

Analysis of radioprotective effect of respiratory hypoxia on hemopoietic tissue and enhancement o... more Analysis of radioprotective effect of respiratory hypoxia on hemopoietic tissue and enhancement of this effect by hemopoietic activation. In mice breathing hypoxic gas mixture during total body gamma irradiation the recovery of pluripotent and committed granulocyte-macrophage progenitor cells and animal lethality were determined. In mice forced to breathe 10% O2 and 8% O2 during irradiation, the oxygen tension in the spleen decreased to 40% and 20%, respectively, of control values. Hypoxia mitigated the lethal effect of gamma-rays and improved the recovery of hemopoiesis in compartments of pluripotent and committed progenitor cells. Enhancement of the proliferative activity in hemopoietic tissue by a cytokine (rmGM-CSF) or an immunomodulator (dextran sulfate) increased the effect of hypoxic radioprotection, while elimination of proliferative cells by hydroxyurea decreased the radioprotective effect. Adaptation of experimental animals to hypoxic conditions was found to reduce the radioprotective effect without influencing tissue partial oxygen pressure lowered by hypoxic conditions. The data presented confirm the radioprotective effect of 10% and 8% O2 respiratory hypoxia on hemopoiesis. These findings may represent a way out for further experimental and clinical research aimed at considering differential protection of various tissues by hypoxia.

Radiation Research, 2006

clooxygenase 2 Inhibitor, Supports Hematopoietic Recovery in Gamma-Irradiated Mice. Radiat. Res. ... more clooxygenase 2 Inhibitor, Supports Hematopoietic Recovery in Gamma-Irradiated Mice. Radiat. Res. 166, 556-560 (2006).

Radiation Research, 2000

The frequency of micronucleated polychromatic erythrocytes (PCEs) in mouse bone marrow was assess... more 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%).

Radiation and Environmental Biophysics, 2014

There exists a requirement for drugs which would be useful in therapy of an acute radiation damag... more There exists a requirement for drugs which would be useful in therapy of an acute radiation damage of a mammalian organism. The aim of the study was to evaluate survival parameters in mice exposed to a lethal c-ray dose of 8.5 Gy and treated with single doses of an adenosine A 3 receptor agonist, IB-MECA, or a cyclooxygenase-2 (COX-2) inhibitor, meloxicam, administered alone or in a combination early after irradiation, i.e., 0.5 and 1 h post-irradiation, respectively. The assessed parameters were the mean survival time (MST) and the cumulative percentage 30-day survival (CPS). Administrations of single intraperitoneal doses of either IB-MECA 0.5 h post-irradiation or meloxicam 1 h post-irradiation resulted in statistically significant increases of MST in comparison with the control irradiated mice. Combined administration of IB-MECA and meloxicam was found to be the only treatment statistically enhancing the parameter of CPS and to lead to the most expressive increase in MST of the experimental mice. The findings add new knowledge on the action of an adenosine A 3 receptor agonist and a COX-2 inhibitor in an irradiated mammalian organism and suggest the potential of both the investigated drugs in the treatment of the acute radiation damage.

Molecules, 2011

The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopo... more The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopoietic functions. The studies carried out utilized either non-selective activation of adenosine receptors induced by elevation of extracellular adenosine or by administration of synthetic adenosine analogs having various proportions of selectivity for a particular receptor. Numerous studies have described stimulatory effects of non-selective activation of adenosine receptors, manifested as enhancement of proliferation of cells at various levels of the hematopoietic hierarchy. Subsequent experimental approaches, considering the hematopoiesis-modulating action of adenosine receptor agonists with a high level of selectivity to individual adenosine receptor subtypes, have revealed differential effects of various adenosine analogs. Whereas selective activation of A 1 receptors has resulted in suppression of proliferation of hematopoietic progenitor and precursor cells, that of A 3 receptors has led to stimulated cell proliferation in these cell compartments. Thus, A 1 and A 3 receptors have been found to play a homeostatic role in suppressed and regenerating hematopoiesis. Selective activation of adenosine A 3 receptors has been found to act curatively under conditions of drug-and radiation-induced myelosuppression. The findings in these and further research areas will be summarized and mechanisms of hematopoiesis-modulating action of adenosine receptor agonists will be discussed.

Two adenosine receptor agonists, N 6-(3-iodobenzyl)adenosine- 59-N-methyluronamide (IB-MECA) and ... more Two adenosine receptor agonists, N 6-(3-iodobenzyl)adenosine- 59-N-methyluronamide (IB-MECA) and N 6-cyclopentyladenosine (CPA), which selectively activate adenosine A3 and A1 receptors, respectively, were tested for their ability to influence prolifer- ation of granulocytic and erythroid cells in femoral bone marrow of mice using morphological criteria. Agonists were given intraperitoneally to mice in repeated isomolar doses of 200 nmol/kg. Three variants of

Neoplasma

Nordihydroguaiaretic acid (NDGA) and esculetin, both nonspecific inhibitors of lipoxygenases (LOX... more Nordihydroguaiaretic acid (NDGA) and esculetin, both nonspecific inhibitors of lipoxygenases (LOX), were found to suppress expressively the in vitro proliferation of fibrosarcoma cells G5:113 in concentrations ranging from 10 to 50 microM. Subsequent flow-cytometric analysis of the cell cycle showed that both these drugs significantly decreased the percentage proportion of cells in the G0/G1-phase and simultaneously increased significantly this proportion in the S-phase. No apoptosis was detected in the whole range of concentrations studied, from 2.5 to 50 mM. On the contrary, in experiments in vivo, neither NDGA nor esculetin had any curative effect if they were repeatedly injected intraperitoneally (i.p.) into mice bearing tumors growing from subcutaneously (s.c.) transplanted G5:113 cells. Pretreatment of the fibrosarcoma cells with NDGA or esculetin in vitro preceding their s.c. transplantation into mice did not result in suppression of the tumor growth, either. Finally, if G5:113 cells were injected intravenously and the mice were subsequently treated repeatedly with i.p. injections of NDGA, decreased survival and increased number of surface lung metastases were observed in the NDGA-treated group. Thus the suppressive action of inhibitors of LOX on the growth of fibrosarcoma cells in vitro was not reflected in their anti-tumor effects in vivo.

Physiological research / Academia Scientiarum Bohemoslovaca

The present studies investigated changes in expression of mRNA for adenosine A 1 , A 2a , A 2b , ... more The present studies investigated changes in expression of mRNA for adenosine A 1 , A 2a , A 2b , and A 3 receptors in samples of HL-60 promyelocytic cells differing in the actual presence of cells in various phases of the cell cycle induced by the double thymidine block method. Realtime PCR technique was used for obtaining data on mRNA expression. Statistical analysis of the data revealed that the mRNA expression of adenosine A 1 , A 2a , and A 3 receptors is dependent on the cell cycle phase. G 0 /G 1 and G 2 /M phases were characterized by a higher mRNA expression of adenosine A 1 receptors and a lower one of adenosine A 2a and A 3 receptors whereas the opposite was true for the S phase. Interestingly, expression of mRNA of the adenosine A 2b receptors was independent on the cell cycle phase. The results indicate the plasticity of mRNA expression of adenosine receptors in the investigated promyelocytic cells and its interaction with physiological mechanisms of the cell cycle.

Central European Journal of Biology, 2006

Inhibitors of prostaglandin production, designated as classical non-steroidal antiinflammatory dr... more Inhibitors of prostaglandin production, designated as classical non-steroidal antiinflammatory drugs (NSAIDs) and acting on the base of non-selective inhibition of cyclooxygenases, have been found in numerous studies to potentiate recovery of perturbed haematopoiesis by removing the negative feedback control mediated by prostaglandins. However, classical NSAIDs show pronounced undesirable gastrointestinal side effects, which limits the possibility of their utilization for various pathophysiological states including myelosuppression. Specific cyclooxygenase-2 (COX-2) inhibitors, targeted at selective inhibition of this inducible cyclooxygenase isoform and having much better gastrointestinal side effect profile, have been found in recent studies to retain the haematopoiesisstimulating effects of classical NSAIDs. These results suggest that the indication spectrum of selective COX-2 inhibitors may be extended to the indication of myelosuppression of various etiology. Combining the anti-tumour and haematopoiesis-stimulating activities in a single COX-2 inhibitor may have a positive clinical impact.

Purinergic signalling, 2015

Adenosine A3 receptor knockout (A3AR KO) mice and their wild-type (WT) counterparts were compared... more Adenosine A3 receptor knockout (A3AR KO) mice and their wild-type (WT) counterparts were compared from the point of view of their abilities to survive exposures to lethal doses of γ-radiation belonging to the range of radiation doses inducing the bone marrow acute radiation syndrome. Parameters of cumulative 30-day survival (experiment using a midlethal radiation dose) or cumulative 11-day survival (experiment using an absolutely lethal radiation dose), and of mean survival time were evaluated. The values of A3AR KO mice always reflected their higher survival in comparison with WT ones, the P values being above the limit for statistical significance after the midlethal radiation dose and standing for statistical significance after the absolutely lethal radiation dose. This finding was considered surprising, taking into account the previously obtained findings on defects in numbers and functional properties of peripheral blood cells in A3AR KO mice. Therefore, previous hematological ...

Physiological research / Academia Scientiarum Bohemoslovaca, 2010

Expression of mRNA for adenosine receptor subtypes A(1), A(2a), A(2b), and A(3) in normal and lip... more Expression of mRNA for adenosine receptor subtypes A(1), A(2a), A(2b), and A(3) in normal and lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages has been investigated using the method of quantitative real-time polymerase chain reaction. The results have shown a very low, unquantifiable expression of adenosine A(1) receptor mRNA in both normal and LPS-activated macrophages. The other three adenosine receptor mRNAs have been found to be expressed at various but always quantifiable levels. Activation of the macrophages by LPS induced upregulation of the expression of adenosine receptor A(2a) and A(2b) mRNA, whereas the expression of adenosine receptor A(3) mRNA was downregulated. Unstimulated macrophages exhibited a high expression of the A(2b) adenosine receptor mRNA. The findings are discussed from the point of view of the antiinflammatory and hematopoiesis-stimulating roles of the adenosine receptor signaling.

International journal of immunopharmacology, 2000

It has been demonstrated that the synthetic immunostimulatory compound, adamantylamide dipeptide ... more It has been demonstrated that the synthetic immunostimulatory compound, adamantylamide dipeptide (AdDP) produces hematopoiesis-stimulating effects in mice exposed to sublethal doses of ionizing radiation and increases survival in experimental animals irradiated with a lethal dose. These findings might suggest contingent extension of clinical indications for the administration of AdDP for the conditions of hematopoietic suppression, especially in oncology.

International journal of immunopharmacology

Protection from undesirable effects of radiotherapy or chemotherapy, primarily from myelosuppress... more Protection from undesirable effects of radiotherapy or chemotherapy, primarily from myelosuppression, remains still a crucial problem to be studied. Attention has been therefore paid to various immunomodulatory agents that through the monocyte/macrophage system induced production of cytokines, which can induce and operate restoration of haemopoiesis and thus act radioprotectively. Some synthetic analogues of MDP free of undesirable side-effects, were synthesized in the Czech Republic. Lipophilic beta-D-GlcNstearoyl-(1- > 4)-norMurNAc-L-Abu-D-isoGln (DDD-St) was designed to be easily entrapped into liposomes and this liposomal DDD-St protected efficiently mice against irradiation, when administered i.p., i.v. or s.c. 24 h prior to lethal irradiation (survival rate in the range of 30-80% compared with 0% in control). Especially the subcutaneous application of liposomal DDD-St was very efficient. The parameters characteristic of recovery of haemopoiesis in bone marrow on day 10 afte...

International journal of immunopharmacology

Glucan, a beta-1,3-linked polyglucose derived from the yeast Saccharomyces cerevisiae, is a broad... more Glucan, a beta-1,3-linked polyglucose derived from the yeast Saccharomyces cerevisiae, is a broad spectrum enhancer of host defense mechanisms stimulating humoral and cell-mediated immunity. On the basis of these features, glucan has been tested by the authors' research group in experiments on gamma-irradiated mice. Two glucan forms, particulate and soluble, have been studied. Attention has been focused on various application regimens in relation to the time of irradiation (pre- or postirradiation application), the possibilities of using glucan in various radiation regimens (single or repeated irradiation), combined pharmacological therapy (joint administration of glucan with cystamine or inhibitors of prostaglandin synthesis), and on the negative side effects of therapy with glucan. Some studies included also experiments on unirradiated mice. The results have demonstrated the ability of glucan to influence positively the course of the acute radiation disease. Stimulation of hem...

Biomedicine & Pharmacotherapy, 2007

The present study was performed to define the optimum conditions of the stimulatory action of the... more The present study was performed to define the optimum conditions of the stimulatory action of the adenosine A3 receptor agonist, N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA), on bone marrow hematopoiesis in mice. Effects of 2-day treatment with IB-MECA given at single doses of 200nmol/kg twice daily were investigated in normal mice and in mice whose femoral bone marrow cells were either depleted or regenerating

International Journal of Immunopharmacology, 1997

The influence of dialyzable extract from human leukocytes (DLE) on the in vitro growth of the gra... more The influence of dialyzable extract from human leukocytes (DLE) on the in vitro growth of the granulocyte-macrophage colony-forming cell (GM-CFC) colonies from progenitors of mouse bone marrow cells was studied. DLE alone did not induce the colony growth but it modulated the number of colonies if administered together with a colony-stimulating factor (CSF).

International Journal of Immunopharmacology, 2000

Dialyzed leukocyte extract (DLE) (Immodin SEVAC, Czech Republic) was shown to enhance the recover... more Dialyzed leukocyte extract (DLE) (Immodin SEVAC, Czech Republic) was shown to enhance the recovery of the pools of hemopoietic stem cells (CFUs) and of granulocyte±macrophage hemopoietic progenitor cells (GM-CFC) in the bone marrow in vivo, as well as to increase the numbers of leukocytes and thrombocytes in the peripheral blood of mice exposed to a sublethal dose of gamma-rays, with an ensuing increase in the numbers of mice surviving the lethal radiation dose. In experiments performed in vitro, DLE or sera of mice administered with DLE were added to cultures of intact mouse bone marrow cells containing suboptimal concentrations of hemopoietic stimulatory cytokines, namely recombinant mouse interleukin-3 (rmIL-3) or recombinant mouse granulocyte±macrophage colony-stimulating factor (rmGM-CSF); under these experimental conditions, both DLE and sera of mice administered DLE were found to increase the counts of GM-CFC colonies in the cultures. It can be hypothesized on the basis of the ®ndings obtained in vitro that the described co-stimulating activity (CoSA) of DLE may play a role also under in vivo conditions; the enhancement of the recovery of hemopoiesis suppressed by ionizing radiation may be due to a co-operation of the stimulatory eects of DLE with the action of cytokines endogenously produced in irradiated tissues. 7

International Journal of Immunopharmacology, 1995

The hemopoiesis-enhancing ability of a soluble glucan derivative, i.e. carboxymethylglucan (CMG),... more The hemopoiesis-enhancing ability of a soluble glucan derivative, i.e. carboxymethylglucan (CMG), was investigated in gamma-irradiated mice. Attention was focused on the usefulness of its single or repeated postirradiation administration. CMG was administered i.p. at (a) single dose of 6 mg 2 h postirradiation, (b) four 6 mg doses in the first 4 days postirradiation, (c) four 1.5 mg doses at the same time intervals. Indices of granulopoiesis and inflammatory side effects (liver weight increase and hepatic granulomas) were investigated in mice irradiated with a sublethal dose of 7 Gy. All three CMG-treated groups of mice were found to exhibit enhanced hemopoietic recovery in comparison with the controls. Although the mice repeatedly given the 6 mg CMG doses showed the most rapid recoveries of all the evaluated parameters of granulopoiesis, the most pronounced hepatic side effects were found in these mice, too. When survival of mice was recorded in lethally (9 Gy) irradiated animals, the best protective response were obtained following the repeated administration of the 1.5 mg CMG dose, the survival by day 30 in this group being significantly higher not only in comparison with the controls but also with the mice repeatedly given the 6 mg dose of CMG. The results suggest that the postirradiation CMG administration can be useful for enhancing radiation suppressed hemopoiesis. However, repeated larger CMG doses may produce side effects which compromise the overall survival of irradiated mice.

Cancer Investigation, 2002

Strahlentherapie und Onkologie, 2001

Analysis of radioprotective effect of respiratory hypoxia on hemopoietic tissue and enhancement o... more Analysis of radioprotective effect of respiratory hypoxia on hemopoietic tissue and enhancement of this effect by hemopoietic activation. In mice breathing hypoxic gas mixture during total body gamma irradiation the recovery of pluripotent and committed granulocyte-macrophage progenitor cells and animal lethality were determined. In mice forced to breathe 10% O2 and 8% O2 during irradiation, the oxygen tension in the spleen decreased to 40% and 20%, respectively, of control values. Hypoxia mitigated the lethal effect of gamma-rays and improved the recovery of hemopoiesis in compartments of pluripotent and committed progenitor cells. Enhancement of the proliferative activity in hemopoietic tissue by a cytokine (rmGM-CSF) or an immunomodulator (dextran sulfate) increased the effect of hypoxic radioprotection, while elimination of proliferative cells by hydroxyurea decreased the radioprotective effect. Adaptation of experimental animals to hypoxic conditions was found to reduce the radioprotective effect without influencing tissue partial oxygen pressure lowered by hypoxic conditions. The data presented confirm the radioprotective effect of 10% and 8% O2 respiratory hypoxia on hemopoiesis. These findings may represent a way out for further experimental and clinical research aimed at considering differential protection of various tissues by hypoxia.

Radiation Research, 2006

clooxygenase 2 Inhibitor, Supports Hematopoietic Recovery in Gamma-Irradiated Mice. Radiat. Res. ... more clooxygenase 2 Inhibitor, Supports Hematopoietic Recovery in Gamma-Irradiated Mice. Radiat. Res. 166, 556-560 (2006).

Radiation Research, 2000

The frequency of micronucleated polychromatic erythrocytes (PCEs) in mouse bone marrow was assess... more 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%).

Radiation and Environmental Biophysics, 2014

There exists a requirement for drugs which would be useful in therapy of an acute radiation damag... more There exists a requirement for drugs which would be useful in therapy of an acute radiation damage of a mammalian organism. The aim of the study was to evaluate survival parameters in mice exposed to a lethal c-ray dose of 8.5 Gy and treated with single doses of an adenosine A 3 receptor agonist, IB-MECA, or a cyclooxygenase-2 (COX-2) inhibitor, meloxicam, administered alone or in a combination early after irradiation, i.e., 0.5 and 1 h post-irradiation, respectively. The assessed parameters were the mean survival time (MST) and the cumulative percentage 30-day survival (CPS). Administrations of single intraperitoneal doses of either IB-MECA 0.5 h post-irradiation or meloxicam 1 h post-irradiation resulted in statistically significant increases of MST in comparison with the control irradiated mice. Combined administration of IB-MECA and meloxicam was found to be the only treatment statistically enhancing the parameter of CPS and to lead to the most expressive increase in MST of the experimental mice. The findings add new knowledge on the action of an adenosine A 3 receptor agonist and a COX-2 inhibitor in an irradiated mammalian organism and suggest the potential of both the investigated drugs in the treatment of the acute radiation damage.